Biaryl Substituted Pyrazinones as Sodium Channel Blockers

ABSTRACT

Biaryl substituted pyrazinone compounds represented by Formula I, or pharmaceutically acceptable salts thereof. Pharmaceutical compositions comprise an effective amount of the instant compounds, either alone, or in combination with one or more other therapeutically active compounds, and a pharmaceutically acceptable carrier. Methods of treating conditions associated with, or caused by, sodium channel activity, including, for example, acute pain, chronic pain, visceral pain, inflammatory pain, neuropathic pain, urinary incontinence, itchiness, allergic dermatitis, epilepsy, irritable bowel syndrome, depression, anxiety, multiple sclerosis, and bipolar disorder, comprise administering an effective amount of the present compounds, either alone, or in combination with one or more other therapeutically active compounds. A method of administering local anesthesia comprises administering an effective amount of a compound of the instant invention, either alone, or in combination with one or more other therapeutically active compounds, and a pharmaceutically acceptable carrier.

FIELD OF THE INVENTION

The present invention is directed to a series of biaryl substitutedpyrazinone compounds. In particular, this invention is directed tobiaryl substituted pyrazinones that are sodium channel blockers usefulfor the treatment of chronic and neuropathic pain. The compounds of thepresent invention are also useful for the treatment of other conditions,including disorders of bladder function, pruritis, itchiness, allergicdermatitis and disorders of the central nervous system (CNS) such asepilepsy, manic depression, bipolar disorder, depression, anxiety anddiabetic neuropathy.

BACKGROUND OF THE INVENTION

Voltage-gated ion channels allow electrically excitable cells togenerate and propagate action potentials and therefore are crucial fornerve and muscle function. Sodium channels play a special role bymediating rapid depolarization, which constitutes the rising phase ofthe action potential and in turn activates voltage-gated calcium andpotassium channels. Voltage-gated sodium channels represent a multigenefamily. Nine sodium channel subtypes have been cloned and functionallyexpressed to date. [Clare, J. J., Tate, S. N., Nobbs, M. & Romanos, M.A. Voltage-gated sodium channels as therapeutic targets. Drug DiscoveryToday 5, 506-520 (2000)]. They are differentially expressed throughoutmuscle and nerve tissues and show distinct biophysical properties. Allvoltage-gated sodium channels are characterized by a high degree ofselectivity for sodium over other ions and by their voltage-dependentgating. [Catterall, W. A. Structure and function of voltage-gated sodiumand calcium channels. Current Opinion in Neurobiology 1, 5-13 (1991)].At negative or hyperpolarized membrane potentials, sodium channels areclosed. Following membrane depolarization, sodium channels open rapidlyand then inactivate. Sodium channels only conduct currents in the openstate and, once inactivated, have to return to the resting state,favored by membrane hyperpolarization, before they can reopen. Differentsodium channel subtypes vary in the voltage range over which theyactivate and inactivate as well as in their activation and inactivationkinetics.

Sodium channels are the target of a diverse array of pharmacologicalagents, including neurotoxins, antiarrhythmics, anticonvulsants andlocal anesthetics. [Clare, J. J., Tate, S. N., Nobbs, M. & Romanos, M.A. Voltage-gated sodium channels as therapeutic targets. Drug DiscoveryToday 5, 506-520 (2000)]. Several regions in the sodium channelsecondary structure are involved in interactions with these blockers andmost are highly conserved. Indeed, most sodium channel blockers known todate interact with similar potency with all channel subtypes.Nevertheless, it has been possible to produce sodium channel blockerswith therapeutic selectivity and a sufficient therapeutic window for thetreatment of epilepsy (e.g. lamotrigine, phenytoin and carbamazepine)and certain cardiac arrhythmias (e.g. lignocaine, tocainide andmexiletine).

It is well known that the voltage-gated Na+ channels in nerves play acritical role in neuropathic pain. Injuries of the peripheral nervoussystem often result in neuropathic pain persisting long after theinitial injury resolves. Examples of neuropathic pain include, but arenot limited to, postherpetic neuralgia, trigeminal neuralgia, diabeticneuropathy, chronic lower back pain, phantom limb pain, pain resultingfrom cancer and chemotherapy, chronic pelvic pain, complex regional painsyndrome and related neuralgias. It has been shown in human patients aswell as in animal models of neuropathic pain, that damage to primaryafferent sensory neurons can lead to neuroma formation and spontaneousactivity, as well as evoked activity in response to normally innocuousstimuli. [Carter, G. T. and B. S. Galer, Advances in the management ofneuropathic pain. Physical Medicine and Rehabilitation Clinics of NorthAmerica, 2001. 12(2): p. 447-459). The ectopic activity of normallysilent sensory neurons is thought to contribute to the generation andmaintenance of neuropathic pain. Neuropathic pain is generally assumedto be associated with an increase in sodium channel activity in theinjured nerve. [Baker, M. D. and J. N. Wood, Involvement of Na channelsin pain pathways. TRENDS in Pharmacological Sciences, 2001. 22(1): p.27-31].

Indeed, in rat models of peripheral nerve injury, ectopic activity inthe injured nerve corresponds to the behavioral signs of pain. In thesemodels, intravenous application of the sodium channel blocker and localanesthetic lidocaine can suppress the ectopic activity and reverse thetactile allodynia at concentrations that do not affect general behaviorand motor function. [Mao, J. and L. L. Chen, Systemic lidocaine forneuropathic pain relief. Pain, 2000. 87: p. 7-17]. These effectiveconcentrations were similar to concentrations shown to be clinicallyefficacious in humans. [Tanelian, D. L. and W. G. Brose, Neuropathicpain can be relieved by drugs that are use-dependent sodium channelblockers: lidocaine, carbamazepine and mexiletine. Anesthesiology, 1991.74(5): p. 949-951]. In a placebo-controlled study, continuous infusionof lidocaine caused reduced pain scores in patients with peripheralnerve injury, and in a separate study, intravenous lidocaine reducedpain intensity associated with postherpetic neuralgia (PHN). [Mao, J.and L. L. Chen, Systemic lidocaine for neuropathic pain relief. Pain,2000. 87: p. 7-17. Anger, T., et al., Medicinal chemistry of neuronalvoltage-gated sodium channel blockers. Journal of Medicinal Chemistry,2001. 44(2): p. 115-137]. Lidoderm®, lidocaine applied in the form of adermal patch, is currently the only FDA approved treatment for PHN.[Devers, A. and B. S. Galer, Topical lidocaine patch relieves a varietyof neuropathic pain conditions: an open-label study. Clinical Journal ofPain, 2000. 16(3): p. 205-208].

In addition to neuropathic pain, sodium channel blockers have clinicaluses in the treatment of epilepsy and cardiac arrhythmias. Recentevidence from animal models suggests that sodium channel blockers mayalso be useful for neuroprotection under ischaemic conditions caused bystroke or neural trauma and in patients with multiple sclerosis (MS).[Clare, J. J., et al. And Anger, T., et al.].

International Patent Publication WO 00/57877 describes aryl substitutedpyrazoles, imidazoles, oxazoles, thiazoles, and pyrroles and their usesas sodium channel blockers. International Patent Publication WO 01/68612describes aryl substituted pyridines, pyrimidines, pyrazines andtriazines and their uses as sodium channel blockers. InternationalPatent Publication WO 99/32462 describes triazine compounds for thetreatment for CNS disorders. However, there remains a need for novelcompounds and compositions that therapeutically block neuronal sodiumchannels with less side effects and higher potency than currently knowncompounds.

SUMMARY OF THE INVENTION

The present invention is directed to biaryl substituted pyrazinonecompounds which are sodium channel blockers useful for the treatment ofchronic and neuropathic pain. The compounds of the present invention arealso useful for the treatment of other conditions, including urinaryincontinence, itchiness, allergic dermatitis, and disorders of the CNSsuch as anxiety, depression, epilepsy, manic depression and bipolardisorder. This invention also provides pharmaceutical compositionscomprising a compound of the present invention, either alone, or incombination with one or more therapeutically active compounds, and apharmaceutically acceptable carrier.

This invention further comprises methods for the treatment of acutepain, chronic pain, visceral pain, inflammatory pain, neuropathic pain,urinary incontinence, itchiness, allergic dermatitis, and disorders ofthe CNS including, but not limited to, epilepsy, manic depression,depression, anxiety and bipolar disorder comprising administering thecompounds and pharmaceutical compositions of the present invention.

DETAILED DESCRIPTION OP THE INVENTION

The present invention comprises compounds represented by Formula (I):

or pharmaceutically acceptable salts thereof, wherein

-   R¹ and R² each independently is-   (a) H,-   (b) C₁-C₆-alkyl, optionally substituted with one or more    substituents selected from the group consisting of: F, CF₃, OH,    NR^(a)R^(b), COOH, CONR^(a)R^(b), SO₂NR^(a)R^(b), C(═NH)NH₂,    tetrazolyl, triazolyl, oxazolyl, oxadiazolyl, isooxazolyl,    thiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, phenyl,    piperidinyl, morpholinyl, pyrrolidinyl and piperazinyl,-   (c) —C(═O)R^(a), COOR^(a), CONR^(a)R^(b),-   (d) —C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl,-   (e) NR^(a)R^(b), —N(COR^(a))R^(b), —N(SO₂R^(a))R^(b), or-   (f) tetrazolyl, triazolyl, oxazolyl, oxadiazolyl, isooxazolyl,    thiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, phenyl,    piperidinyl, morpholinyl, pyrrolidinyl or piperazinyl, any of which    is optionally substituted with 1-3 substituents independently    selected from the group consisting of: F, Cl, Br, I and CN;-   R^(a) is-   (a) H,-   (b) C₁-C₆-alkyl, optionally substituted with one or more    substituents independently selected from the group consisting of CF₃    and O—(C₁-C₄)alkyl,-   (c) C₀-C₄-alkyl-(C₁-C₄)-perfluoroalkyl,-   (d) NH₂,-   (e) C₁-C₄-alkyl-phenyl, C₁-C₄-alkyl-pyridyl, or-   (f) C₃-C₇-cycloalkyl, optionally substituted with one or more    substituents selected from the group consisting of: F, Cl, Br, OH,    —O—C₁-C₄-alkyl, and C₁-C₄-alkyl;-   R^(b) is-   (a) H, or-   (b) C₁-C₆-alkyl;-   R³ is:-   (a) H,-   (b) —C₁-C₄-alkyl, optionally substituted with one or more    substituents independently selected from the group consisting of: F,    CF₃, Cl, N, OH, O—(C₁-C₄)alkyl, S(O)₀₋₂—(C₁-C₄)alkyl,    O—CONR^(a)R^(b), NR^(a)R^(b), N(R^(a))CONR^(a)R^(b), COOR^(a), CN,    CONR^(a)R^(b), SO₂NR^(a)R^(b), N(R^(a))SO₂NR^(a)R^(b), —C(═NH)NH₂,    tetrazolyl, triazolyl, imidazolyl, oxazolyl, oxadiazolyl,    isooxazolyl, thiazolyl, furyl, thienyl, pyrazolyl, pyrrolyl,    pyridyl, pyrimidinyl, pyrazinyl, phenyl, piperidinyl, morpholinyl,    pyrrolidinyl and piperazinyl,    -   or R^(a) and R^(b), together with N to which they are attached,        may form a C₃-C₇-Cycloalkyl or a C₃-C₇-heterocycloalkyl, wherein        said cycloalkyl and heterocycloalkyl is optionally substituted        with one or more substituents selected from the group consisting        of: F, Cl, Br, OH, —O—C₁-C₄-alkyl, and C₁-C₄-alkyl,-   (c) —C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl,-   (d) C₁-C₄-alkyl-C(═O)—R^(a),    —C₁-C₄-alkyl-C(═O)—C₁-C₄-perfluoroalkyl, or-   (e) —C₁-C₄-alkyl-C₃-C₇-Cycloalkyl, wherein said cycloalkyl is    optionally substituted with one or more substituents selected from    the group consisting of: F, Cl, Br, OH, —O—C₁-C₄-alkyl, and    C₁-C₄-alkyl;-   R⁴ and R⁵ each independently is:-   (a) H,-   (b) —C₁-C₆-alkyl, optionally substituted with one or more    substituents independently selected from the group consisting of: F,    CF₃ and —O—(C₁-C₄)alkyl,-   (c) —O—C₀-C₆-alkyl, —O-phenyl, —O—C₁-C₄-alkyl-phenyl, —O-pyridyl,    —O—C₁-C₄-alkyl-pyridyl, wherein phenyl and pyridyl are optionally    substituted with 1-3 substituents independently selected from the    group consisting of: F, Cl, Br, I and CN,-   (d) —C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl,    —O—C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl, or-   (e) F, Cl, Br, I; and-   R⁶, R⁷ and R⁸ each independently is:-   (a) H,-   (b) C₁-C₆-alkyl,-   (c) —O—C₁-C₆-alkyl, optionally substituted with one or more    substituents independently selected from the group consisting of: F    and CF₃,-   (d) —C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl,    —O—C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl,-   (e) —O-phenyl, —O—C₁-C₄-alkyl-phenyl, —O-pyridyl,    —O—C₁-C₄-alkyl-pyridyl, wherein phenyl and pyridyl are optionally    substituted with 1-3 substituents independently selected from the    group consisting of: F, Cl, Br, I, and CN, or-   (f) F, Cl, Br, I, —OR^(a), phenyl or pyridyl, wherein phenyl and    pyridyl are optionally substituted with one or more substituents    independently selected from the group consisting of: F, Cl, Br, I    and CN,

with the proviso that when R⁶ and R⁷ are present on adjacent carbonatoms, R⁶ and R⁷, together with the benzene ring to which they areattached, may form a bicyclic aromatic ring selected from the groupconsisting of: naphthyl, quinolinyl and benzothiazolyl, any aromaticring of which is optionally substituted with 1-4 substituentsindependently selected from F, Cl, Br, I and CN.

In one aspect, the present invention provides a compound described bythe chemical Formula (I), or a pharmaceutically acceptable salt thereof,wherein

R⁶ is other than H and is attached at the ortho position, and all othervariables are as previously defined.

In an embodiment of this one aspect, the present invention provides acompound described by the chemical Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein

R¹ is H, COOR^(a) or CONR^(a)R^(b), and all other variables are aspreviously defined.

In a second aspect, the present invention provides sodium channelblockers described by the chemical Formula (I), or pharmaceuticallyacceptable salts thereof, which include compounds of the Formula Ia:

wherein

-   R⁶ is OR^(a) or C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl, and all other    variables are as previously defined.

In a third aspect, the present invention provides sodium channelblockers described by the chemical Formula (I), or pharmaceuticallyacceptable salts thereof, which include compounds of the Formula Ib:

wherein

-   R⁶ is OR^(a) or C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl;-   R⁷ is H, F, Cl, Br or I; and all other variables are as previously    defined.

In a fourth aspect, the present invention provides sodium channelblockers described by the chemical Formula (I), or pharmaceuticallyacceptable salts thereof, which include compounds of the Formula Ic:

wherein

-   R⁴ and R⁵ each independently is H, F, Cl, Br or I;-   R⁶ is OR^(a) or C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl;-   R⁷ is H, F, Cl, Br or I; and all other variables are as previously    defined.

In a fifth aspect, the present invention provides sodium channelblockers described by the chemical Formula (I), or pharmaceuticallyacceptable salts thereof, which include compounds of the Formula Id:

wherein

-   R⁴ is F, Cl, Br or I;-   R⁶ is OR^(a) or C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl;-   R⁷ is H, F, Cl, Br or I; and all other variables are as previously    defined.

In a sixth aspect, the present invention provides sodium channelblockers described by the chemical Formula (I), or pharmaceuticallyacceptable salts thereof, which include compounds of the Formula Ie:

wherein

-   R¹ is CONH₂;-   R⁶ is OR^(a) or C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl,-   R⁷ is H or F, and all other variables are as previously defined.

As used herein, “alkyl” as well as other groups having the prefix “alk”such as, for example, alkoxy, alkanoyl, alkenyl, and alkynyl meanscarbon chains which may be linear or branched or combinations thereof.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec- and tert-butyl, pentyl, hexyl, and heptyl. “Alkenyl,”“alkynyl” and other like terms include carbon chains containing at leastone unsaturated C-C bond.

The term “cycloalkyl” means carbocycles containing no heteroatoms, andincludes mono-, bi- and tricyclic saturated carbocycles, as well asfused ring systems. Such fused ring systems can include one ring that ispartially or fully unsaturated such as a benzene ring to form fused ringsystems such as benzofused carbocycles. Cycloalkyl includes such fusedring systems as spirofused ring systems. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene,adamantane, indanyl, indenyl, fluorenyl, and1,2,3,4-tetrahydronaphalene. Similarly, “cycloalkenyl” means carbocyclescontaining no heteroatoms and at least one non-aromatic C-C double bond,and include mono-, bi- and tricyclic partially saturated carbocycles, aswell as benzofused cycloalkenes. Examples of cycloalkenyl includecyclohexenyl, and indenyl. The term “aryl” includes any stablemonocyclic or bicyclic carbon ring of up to 7 members in each ring,wherein at least one ring is aromatic. Examples of aryl include phenyl,naphthyl, indanyl or biphenyl.

The term “cycloalkyloxy,” unless specifically stated otherwise, includesa cycloalkyl group connected by a short C₁₋₂alkyl to the oxy connectingatom.

The term “C₀₋₄alkyl” includes alkyls containing 4, 3, 2, 1, or no carbonatoms. An alkyl with no carbon atoms is a hydrogen atom substituent whenthe alkyl is a terminal group and is a direct bond when the alkyl is abridging group.

The term “hetero,” unless specifically stated otherwise, includes one ormore O, S, or N atoms. For example, heterocycloalkyl and heteroarylinclude ring systems that contain one or more O, S, or N atoms in thering, including mixtures of such atoms. The hetero atoms replace ringcarbon atoms. Thus, for example, a C₅-heterocycloalkyl is a five-memberring containing from 4 to no carbon atoms. Examples of heteroarylsinclude pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl,pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl,benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl,benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl,imidazolyl, benzimidazole, oxadiazolyl, thiadiazolyl, triazolyl, andtetrazolyl. Examples of heterocycloalkyls include azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.

The term “heteroC₀₋₄alkyl” means a heteroalkyl containing 3, 2, 1, or nocarbon atoms. However, at least one heteroatom must be present. Thus, asan example, a heteroC₀₋₄alkyl having no carbon atoms but one N atomwould be a —NH— if a bridging group and a —NH₂ if a terminal group.Analogous bridging or terminal groups are clear for an O or Sheteroatom.

The term “amine,” unless specifically stated otherwise, includesprimary, secondary and tertiary amines.

The term “carbonyl,” unless specifically stated otherwise, includes aC₀₋₆alkyl substituent group when the carbonyl is terminal.

The term “halogen” includes fluorine, chlorine, bromine and iodineatoms.

The term “mammal” “mammalian” or “mammals” includes humans, as well asanimals, such as dogs, cats, horses, pigs and cattle.

The term “optionally substituted” is intended to include bothsubstituted and unsubstituted. Thus, for example, optionally substitutedaryl could represent a pentafluorophenyl or a phenyl ring. Further,optionally substituted multiple moieties such as, for example, alkylarylare intended to mean that the alkyl and the aryl groups are optionallysubstituted. If only one of the multiple moieties is optionallysubstituted then it will be specifically recited such as “an alkylaryl,the aryl optionally substituted with halogen or hydroxyl.”

The term “patient” includes mammalian subjects such as humans andanimals. Accordingly, in addition to a human, a patient can be, forexample, a dog, cat, horse, pig or cow.

Compounds described herein may contain one or more double bonds and maythus give rise to cis/trans isomers as well as other conformationalisomers. The present invention includes all such possible isomers aswell as mixtures of such isomers unless specifically stated otherwise.

Compounds described herein can contain one or more asymmetric centersand may thus give rise to diastereoisomers and optical isomers. Thepresent invention includes all such possible diastereoisomers as well astheir racemic mixtures, their substantially pure resolved enantiomers,all possible geometric isomers, and pharmaceutically acceptable saltsthereof. The above chemical Formulas are shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of the chemical Formulas and pharmaceutically acceptablesalts thereof. Further, mixtures of stereoisomers as well as isolatedspecific stereoisomers are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, as well as cyclic amines andsubstituted amines such as naturally occurring and synthesizedsubstituted amines. Other pharmaceutically acceptable organic non-toxicbases from which salts can be formed include ion exchange resins suchas, for example, arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, andtromethamine.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Thepharmaceutical compositions of the present invention comprise compoundsof the invention (or pharmaceutically acceptable salts thereof) as anactive ingredient, a pharmaceutically acceptable carrier, and optionallyone or more additional therapeutic agents or adjuvants. Such additionaltherapeutic agents can include, for example, i) opiate agonists orantagonists, ii) calcium channel antagonists, iii) 5HT receptor agonistsor antagonists, iv) sodium channel antagonists, v) NMDA receptoragonists or antagonists, vi) COX-2 selective inhibitors, vii) NK1antagonists, viii) non-steroidal anti-inflammatory drugs (“NSAID”), ix)selective serotonin reuptake inhibitors (“SSRI”) and/or selectiveserotonin and norepinephrine reuptake inhibitors (“SSNRI”), x) tricyclicantidepressant drugs, xi) norepinephrine modulators, xii) lithium, xiii)valproate, and xiv) neurontin (gabapentin). The instant compositionsinclude compositions suitable for oral, rectal, topical, and parenteral(including subcutaneous, intramuscular, and intravenous) administration,although the most suitable route in any given case will depend on theparticular host, and nature and severity of the conditions for which theactive ingredient is being administered. The pharmaceutical compositionsmay be conveniently presented in unit dosage form and prepared by any ofthe methods well known in the art of pharmacy.

The present compounds and compositions are useful for the treatment ofchronic, visceral, inflammatory and neuropathic pain syndromes. They areuseful for the treatment of pain resulting from traumatic nerve injury,nerve compression or entrapment, postherpetic neuralgia, trigeminalneuralgia, and diabetic neuropathy. The present compounds andcompositions are also useful for the treatment of chronic lower backpain, phantom limb pain, chronic pelvic pain, neuroma pain, complexregional pain syndrome, chronic arthritic pain and related neuralgias,and pain associated with cancer, chemotherapy, HIV and HIVtreatment-induced neuropathy. Compounds of this invention may also beutilized as local anesthetics. The instant compounds may also be usefulin the treatment of disorders of bladder function such as cystitis,bladder detrusor hyper-reflexia, frequent urination and urinaryincontinence, including the prevention or treatment of overactivebladder with symptoms of urge urinary incontinence, urgency, andfrequency. Compounds of this invention are useful for the treatment ofirritable bowel syndrome and related disorders, as well as Crohn'sdisease.

The instant compounds have clinical uses for the treatment of epilepsyand partial and generalized tonic seizures. They are also useful forneuroprotection under ischaemic conditions caused by stroke or neuraltrauma and for treating multiple sclerosis. The present compounds areuseful for the treatment of tachy-arrhythmias. Additionally, the instantcompounds are useful for the treatment of neuropsychiatric disorders,including mood disorders, such as depression or more particularlydepressive disorders, for example, single episodic or recurrent majordepressive disorders and dysthymic disorders, or bipolar disorders, forexample, bipolar I disorder, bipolar II disorder and cyclothymicdisorder; anxiety disorders, such as panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobias, for example, specific animal phobias, social phobias,obsessive-compulsive disorder, stress disorders including post-traumaticstress disorder and acute stress disorder, and generalised anxietydisorders.

The present compounds are also useful for the treatment of pruritis,dermatitis, allergic dermatitis, atopic dermatitis, itchiness, and itchyskin, including the treatment of itchy skin, atopic dermatitis, andallergic dermatitis in animals such as dogs and cats.

It will be appreciated that for the treatment of depression or anxiety,a compound of the present invention may be used in conjunction withother anti-depressant or anti-anxiety agents, such as norepinephrinereuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs),monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamineoxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors(SNRIs), α-adrenoreceptor antagonists, atypical anti-depressants,benzodiazepines, 5-HT_(1A) agonists or antagonists, especially 5-HT_(1A)partial agonists, neurokinin-1 receptor antagonists, corticotropinreleasing factor (CRF) antagonists, and pharmaceutically acceptablesalts thereof.

Further, it is understood that compounds of this invention can beadministered at prophylactically effective dosage levels to prevent theabove-recited conditions and disorders, as well as to prevent otherconditions and disorders associated with sodium channel activity.

Creams, ointments, jellies, solutions, or suspensions containing theinstant compounds can be employed for topical use. Mouth washes andgargles are included within the scope of topical use for the purposes ofthis invention.

Dosage levels from about 0.01 mg/kg to about 140 mg/kg of body weightper day are useful in the treatment of inflammatory and neuropathicpain, or alternatively about 0.5 mg to about 7 g per patient per day.For example, inflammatory pain may be effectively treated by theadministration of from about 0.01 mg to about 75 mg of the compound perkilogram of body weight per day, or alternatively about 0.5 mg to about3.5 g per patient per day. Neuropathic pain may be effectively treatedby the administration of from about 0.01 mg to about 125 mg of thecompound per kilogram of body weight per day, or alternatively about 0.5mg to about 5.5 g per patient per day.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration to humans mayconveniently contain from about 0.5 mg to about 5 g of active agent,compounded with an appropriate and convenient amount of carrier materialwhich may vary from about 5 to about 95 percent of the totalcomposition. Unit dosage forms will generally contain between from about1 mg to about 1000 mg of the active ingredient, typically 25 mg, 50 mg,100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors. Suchpatient-related factors include the age, body weight, general health,sex, and diet of the patient. Other factors include the time and routeof administration, rate of excretion, drug combination, and the severityof the particular disease undergoing therapy.

In practice, the compounds of the invention, or pharmaceuticallyacceptable salts thereof, can be combined as the active ingredient inintimate admixture with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms depending on the form of preparation desired foradministration, e.g., oral or parenteral (including intravenous). Thus,the pharmaceutical compositions of the present invention can bepresented as discrete units suitable for oral administration such ascapsules, cachets or tablets each containing a predetermined amount ofthe active ingredient. Further, the compositions can be presented as apowder, as granules, as a solution, as a suspension in an aqueousliquid, as a non-aqueous liquid, as an oil-in-water emulsion or as awater-in-oil liquid emulsion. In addition to the common dosage forms setout above, the compounds of the invention, or pharmaceuticallyacceptable salts thereof, may also be administered by controlled releasemeans and/or delivery devices. The compositions may be prepared by anyof the methods of pharmacy. In general, such methods include a step ofbringing into association the active ingredient with the carrier thatconstitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both. The product can then be conveniently shaped into the desiredpresentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of Formula I, Ia, Ib, Ic or Id. The compounds of theinvention, or pharmaceutically acceptable salts thereof, can also beincluded in pharmaceutical compositions in combination with one or moretherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents can be used to form oral solidpreparations such as powders, capsules and tablets. Because of theirease of administration, tablets and capsules are the preferred oraldosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.1 mg to about 500 mg of theactive ingredient and each cachet or capsule preferably containing fromabout 0.1 mg to about 500 mg of the active ingredient. Thus, a tablet,cachet, or capsule conveniently contains 0.1 mg, 1 mg, 5 mg, 25 mg, 50mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredienttaken one or two tablets, cachets, or capsules, once, twice, or threetimes daily.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage, and thus should be preserved against the contaminating actionof microorganisms such as bacteria and fungi. The carrier can be asolvent or dispersion medium containing, for example, water, ethanol,polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol),vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, and dusting powder. Further, the compositions can bein a form suitable for use in transdermal devices. These formulationsmay be prepared, utilizing a compound represented of the invention, orpharmaceutically acceptable salts thereof, via conventional processingmethods. As an example, a cream or ointment is prepared by mixinghydrophilic material and water, together with about 5 wt % to about 10wt % of the compound, to produce a cream or ointment having a desiredconsistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid, such as, forexample, where the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, and preservatives (including anti-oxidants). Furthermore,other adjuvants can be included to render the formulation isotonic withthe blood of the intended recipient. Compositions containing a compoundof the invention, or pharmaceutically acceptable salts thereof, can alsobe prepared in powder or liquid concentrate form.

The compounds and pharmaceutical compositions of this invention havebeen found to block sodium channels. Accordingly, an aspect of theinvention is the treatment and prevention in mammals of conditions thatare amenable to amelioration through blockage of neuronal sodiumchannels by administering an effective amount of a compound of thisinvention. Such conditions include, for example, acute pain, chronicpain, visceral pain, inflammatory pain and neuropathic pain. The instantcompounds and compositions are useful for treating and preventing theconditions recited herein, including acute pain, chronic pain, visceralpain, inflammatory pain, urinary incontinence, itchiness, allergicdermatitis, pruritis and neuropathic pain, in humans and non-humanmammals such as dogs and cats. It is understood that the treatment ofmammals other than humans refers to the treatment of clinical conditionsin non-human mammals that correlate to the conditions recited herein.

Further, as described above, the instant compounds can be utilized incombination with one or more therapeutically active compounds. Inparticular, the inventive compounds can be advantageously used incombination with i) opiate agonists or antagonists, ii) calcium channelantagonists, iii) 5HT receptor agonists or antagonists, including5-HT_(1A) agonists or antagonists, and 5-HT_(1A) partial agonists, iv)sodium channel antagonists, v) N-methyl-D-aspartate (NMDA) receptoragonists or antagonists, vi) COX-2 selective inhibitors, vii) neurokininreceptor 1 (NK1) antagonists, viii) non-steroidal anti-inflammatorydrugs (NSAID), ix) selective serotonin reuptake inhibitors (SSRI) and/orselective serotonin and norepinephrine reuptake inhibitors (SSNRI), x)tricyclic antidepressant drugs, xi) norepinephrine modulators, xii)lithium, xiii) valproate, xiv) norepinephrine reuptake inhibitors, xv)monoamine oxidase inhibitors (MAOIs), xvi) reversible inhibitors ofmonoamine oxidase (RIMAs), xvii) □-adrenoreceptor antagonists, xviii)atypical anti-depressants, xix) benzodiazepines, xx) corticotropinreleasing factor (CRF) antagonists, xxi) neurontin (gabapentin), xxii)anticholinergic agents, and xxiii) muscarinic receptor antagonists.

The abbreviations used herein have the following meanings (abbreviationsnot shown here have their meanings as commonly used unless specificallystated otherwise): Ac (acetyl), AIBN (2,2′-azobis(isobutyronitrile)),BINAP (1,1′-bi-2-naphthol), Bn (benzyl), CAMP (cyclicadenosine-3′,5′-monophosphate), DAST ((diethylamino)sulfur trifluoride),DEAD (diethyl azodicarboxylate), DBU(1,8-diazabicyclo[5.4.0]undec-7-ene), DIBAL (diisobutylaluminumhydride), DMAP (4-(dimethylamino)pyridine), DMF (N,N-dimethylformamide),Dppf (1,1′-bis(diphenylphosphino)-ferrocene), EDCI(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), Et3N(triethylamine), GST (glutathione transferase), HMDS(Hexamethyldisilazide), LDA (lithium diisopropylamide), m-CPBA(metachloroperbenzoic acid), MMPP (monoperoxyphthalic acid), MPPM(monoperoxyphthalic acid), Ms (methanesulfonyl; mesyl; or SO2Me), MsO(methanesulfonate or mesylate), NBS (N-bromo succinimide), NSAID(non-steroidal anti-inflammatory drug), o-Tol (ortho-tolyl), OXONE®(2KHSO5.KHSO4.K2SO4), PCC (pyridinium chlorochromate), Pd2(dba)3(Bis(dibenzylideneacetone) palladium(0)), PDC (pyridinium dichromate),PDE (Phosphodiesterase), Ph (Phenyl), Phe (Benzenediyl), PMB(para-methoxybenzyl), Pye (Pyridinediyl), r.t. or RT (room temperature),Rac (Racemic), SAM (aminosulfonyl; sulfonamide or SO2NH2), SEM(2-(trimethylsilyl)ethoxymethoxy), SPA (scintillation proximity assay),TBAF (tetra-n-butylammonium fluoride), Th (2- or 3-thienyl), TFA(trifluoroacetic acid), TFAA (trifluoroacetic acid anhydride), THF(Tetrahydrofuran), Thi (Thiophenediyl), TLC (thin layer chromatography),TMS—CN (triethylsilyl cyanide), TMSI (trimethylsilyl iodide), Tz (1H (or2H)-tetrazol-5-yl), XANTPHOS(4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene), C3H5 (Allyl), Me(methyl), Et (ethyl), n-Pr (normal propyl), i-Pr (isopropyl), n-Bu(normal butyl), i-Butyl (isobutyl), s-Bu (secondary butyl), t-Bu(tertiary butyl), c-Pr (cyclopropyl), c-Bu (cyclobutyl), c-Pen(cyclopentyl), c-Hex (cyclohexyl).

The following in vitro and in vivo assays were used in assessing thebiological activity of the instant compounds.

Compound Evaluation (in vitro Assay):

The identification of inhibitors of the sodium channel is based on theability of sodium channels to cause cell depolarization when sodium ionspermeate through agonist-modified channels. In the absence ofinhibitors, exposure of an agonist-modified channel to sodium ions willcause cell depolarization. Sodium channel inhibitors will prevent celldepolarization caused by sodium ion movement through agonist-modifiedsodium channels. Changes in membrane potential can be determined withvoltage-sensitive fluorescence resonance energy transfer (FRET) dyepairs that use two components, a donor coumarin (CC₂DMPE) and anacceptor oxanol (DiSBAC₂(3)). Oxanol is a lipophilic anion anddistributes across the membrane according to membrane potential. In thepresence of a sodium channel agonist, but in the absence of sodium, theinside of the cell is negative with respect to the outside, oxanol isaccumulated at the outer leaflet of the membrane and excitation ofcoumarin will cause FRET to occur. Addition of sodium will causemembrane depolarization leading to redistribution of oxanol to theinside of the cell, and, as a consequence, to a decrease in FRET. Thus,the ratio change (donor/acceptor) increases after membranedepolarization. In the presence of a sodium channel inhibitor, celldepolarization will not occur, and therefore the distribution of oxanoland FRET will remain unchanged.

Cells stably transfected with the PN1 sodium channel (HEK—PN1) weregrown in polylysine-coated 96-well plates at a density of ca. 140,000cells/well. The media was aspirated, and the cells were washed with PBSbuffer, and incubated with 100 μl of 10 μm CC₂-DMPE in 0.02% pluronicacid. After incubation at 25° C. for 45 min, media was removed and cellswere washed 2× with buffer. Cells were incubated with 100 μl ofDiSBAC₂(3) in TMA buffer containing 20 μm veratridine, 20 nmbrevetoxin-3, and test sample. After incubation at 25° C. for 45 min inthe dark, plates were placed in the VIPR instrument, and thefluorescence emission of both CC₂-DMPE and DiSBAC₂(3) recorded for 10 s.At this point, 100 μl of saline buffer was added to the wells todetermine the extent of sodium-dependent cell depolarization, and thefluorescence emission of both dyes recorded for an additional 20 s. Theratio CC₂-DMPE/DiSBAC₂(3), before addition of saline buffer equals 1. Inthe absence of inhibitors, the ratio after addition of saline bufferis >1.5. When the sodium channel has been completely inhibited by eithera known standard or test compound, this ratio remains at 1. It ispossible, therefore, to titrate the activity of a sodium channelinhibitor by monitoring the concentration-dependent change influorescence ratio.

Electrophysiological Assays (in vitro Assays):

Cell preparation: A HEK-293 cell line stably expressing the PN1 sodiumchannel subtype was established in-house. The cells were cultured in MEMgrowth media (Gibco) with 0.5 mg/Ml G418, 50 units/Ml Pen/Strep and 1 Mlheat-inactivated fetal bovine serum at 37° C. and 10% CO₂. Forelectrophysiological recordings, cells were plated on 35 mm dishescoated with poly-D-lysine.

Whole-cell recordings: HEK-293 cells stably expressing the PN1 sodiumchannel subtype were examined by whole cell voltage clamp (Hamill, etal. Pfluegers Archives 391:85-100 (1981)) using an EPC-9 amplifier andPulse software (HEKA Electronics, Lamprecht, Germany). Experiments wereperformed at room temperature. Electrodes were fire-polished toresistances of 2-4 MΩ. Voltage errors were minimized by seriesresistance compensation, and the capacitance transient was canceledusing the EPC-9's built-in circuitry. Data were acquired at 50 kHz andfiltered at 7-10 kHz. The bath solution consisted of 40 mM NaCl, 120 mMNMDG Cl, 1 mM KCl, 2.7 mM CaCl₂, 0.5 MM MgCl₂, 10 mM NMDG HEPES, Ph 7.4,and the internal (pipet) solution contained 110 mM Cs-methanesulfonate,5 mM NaCl, 20 mM CsCl, 10 mM CsF, 10 mM BAPTA (tetra Cs salt), 10 mM CsHEPES, Ph 7.4.

The following protocols were used to estimate the steady-state affinityof compounds for the resting and inactivated state of the channel (K_(r)and K_(i), respectively):

1. 8 ms test-pulses to depolarizing voltages from −60 Mv to +50 Mv froma holding potential of −90 Mv were used to construct current-voltagerelationships (IV-curves). A voltage near the peak of the IV-curve(typically −10 or 0 Mv) was used as the test-pulse voltage throughoutthe remainder of the experiment.

2. Steady-state inactivation (availability) curves were constructed bymeasuring the current activated during an 8 ms test-pulse following 10 sconditioning pulses to potentials ranging from −120 Mv to −10 Mv.

3. Compounds were applied at a holding potential at which 20-50% of thechannels was inactivated and sodium channel blockage was monitoredduring 8 ms test pulses at 2 s intervals.

4. After the compounds equilibrated, the voltage-dependence ofsteady-state inactivation in the presence of compound was determinedaccording to protocol 2) above. Compounds that block the resting stateof the channel decrease the current elicited during test-pulses from allholding potentials, whereas compounds that primarily block theinactivated state shift the mid-point of the steady-state inactivationcurve. The maximum current at negative holding potentials (I_(max)) andthe difference in the mid-points of the steady-state inactivation curves(ΔV) in control and in the presence of a compound were used to calculateK_(r) and K_(i) using the following equations:

$\begin{matrix}{K_{r} = \frac{\lbrack{Drug}\rbrack*I_{{Max},{Drug}}}{I_{{Max},{Control}} - I_{{Max},{Drug}}}} \\{K_{i} = \frac{\lbrack{Drug}\rbrack}{{\left( {1 + \frac{\lbrack{Drug}\rbrack}{K_{r}}} \right)*^{\frac{{- \Delta}\; V}{k}}} - 1}}\end{matrix}$

In cases where the compound did not affect the resting state, K_(i) wascalculated using the following equation:

$K_{i} = {\frac{\lbrack{Drug}\rbrack}{^{\frac{{- \Delta}\; V}{k}} - 1}.}$

Rat Formalin Paw test (in vivo Assay):

Compounds were assessed for their ability to inhibit the behavioralresponse evoked by a 50 Ml injection of formalin (5%). A metal band wasaffixed to the left hind paw of male Sprague-Dawley rats (Charles River,200-250 g) and each rat was conditioned to the band for 60 min within aplastic cylinder (15 cm diameter). Rats were dosed with either vehicleor a test compound either before (local) or after (systemic) formalinchallenge. For local administration, compounds were prepared in a 1:4:5vehicle of ethanol, PEG400 and saline (EPEGS) and injectedsubcutaneously into the dorsal surface of the left hind paw 5 min priorto formalin. For systemic administration, compounds were prepared ineither a EPEGS vehicle or a Tween80 (10%)/sterile water (90%) vehicleand were injected i.v. (via the lateral tail vein 15 min after formalin)or p.o. (60 min before formalin). The number of flinches was countedcontinuously for 60 min using an automated nociception analyzer (UCSDAnesthesiology Research, San Diego, Calif.). Statistical significancewas determined by comparing the total flinches detected in the early(0-10 min) and late (11-60 min) phase with an unpaired t-test.

In vivo Assay using Rat CFA Model:

Unilateral inflammation was induced with a 0.2 ml injection of completeFreund's adjuvant (CFA: Mycobacterium tuberculosis,.Sigma; suspended inan oil/saline (1:1) emulsion; 0.5 mg Mycobacterium/Ml) in the plantarsurface of the left hindpaw. This dose of CFA produced significant hindpaw swelling but the animals exhibited normal grooming behavior andweight gain over the course of the experiment. Mechanical hyperalgesiawas assessed 3 days after tissue injury using a Randall-Selitto testRepeated Measures ANOVA, followed by Dunnett's Post Hoc test.

SNL: Mechanical Allodynin (in vivo Assay):

Tactile allodynia was assessed with calibrated von Frey filaments usingan up-down paradigm before and two weeks following nerve injury. Animalswere placed in plastic cages with a wire mesh floor and allowed toacclimate for 15 min before each test session. To determine the 50%response threshold, the von Frey filaments (over a range of intensitiesfrom 0.4 to 28.8 g) were applied to the mid-plantar surface for 8 s, oruntil a withdrawal response occurred. Following a positive response, anincrementally weaker stimulus was tested. If there was no response to astimulus, then an incrementally stronger stimulus was presented. Afterthe initial threshold crossing, this procedure was repeated for fourstimulus presentations per animal per test session. Mechanicalsensitivity was assessed 1 and 2 hr post oral administration of the testcompound.

The compounds described in this invention displayed sodium channelblocking activity of from about <0.1 mM to about <50 mM in the in vitroassays described above. It is advantageous that the compounds displaysodium channel blocking activity of <5 mM in the in vitro assays. It ismore advantageous that the compounds display sodium channel blockingactivity of <1 mM in the in vitro assays. It is even more advantageousthat the compounds display sodium channel blocking activity of <0.5 mMin the in vitro assays. It is still more advantageous that the compoundsdisplay sodium channel blocking activity of <0.1 mM in the in vitroassays.

The present compounds can be prepared according to the general Schemesprovided below as well as the procedures provided in the Examples. Thefollowing Schemes and Examples further describe, but do not limit, thescope of the invention.

Unless specifically stated otherwise, the experimental procedures wereperformed under the following conditions: All operations were carriedout at room or ambient temperature; that is, at a temperature in therange of 18-25° C. Evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) witha bath temperature of up to 60° C. The course of reactions was followedby thin layer chromatography (TLC) and reaction times are given forillustration only. Melting points are uncorrected and ‘d’ indicatesdecomposition. The melting points given are those obtained for thematerials prepared as described. Polymorphism may result in isolation ofmaterials with different melting points in some preparations. Thestructure and purity of all final products were assured by at least oneof the following techniques: TLC, mass spectrometry, nuclear magneticresonance (NMR) spectrometry or microanalytical data When given, yieldsare for illustration only. When given, NMR data is in the form of delta(δ) values for major diagnostic protons, given in parts per million(ppm) relative to tetramethylsilane (TMS) as internal standard,determined at 300 MHz, 400 MHz or 500 MHz using the indicated solvent.Conventional abbreviations used for signal shape are: s. singlet; d.doublet; t. triplet; m. multiplet; br. Broad; etc. In addition, “Ar”signifies an aromatic signal. Chemical symbols have their usualmeanings; the following abbreviations are used: v (volume), w (weight),b.p. (boiling point), m.p. (melting point), L (liter(s)), ml(milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol(millimoles), eq (equivalent(s)).

Methods of Synthesis

Compounds of the present invention can be prepared according to theSchemes provided below as well as the procedures provided in theExamples. The substituents are the same as in the above Formulas exceptwhere defined otherwise or otherwise apparent to the ordinary skilledartisan.

The novel compounds of the present invention can be readily synthesizedusing techniques known to those skilled in the art, such as thosedescribed, for example, in Advanced Organic Chemistry, March, 4^(th)Ed., John Wiley and Sons, New York, N.Y., 1992; Advanced OrganicChemistry, Carey and Sundberg, Vol. A and B, 3^(rd) Ed., Plenum Press,Inc., New York, N.Y., 1990; Protective groups in Organic Synthesis,Green and Wuts, 2^(nd) Ed., John Wiley and Sons, New York, N.Y., 1991;Comprehensive Organic Transformations, Larock, VCH Publishers, Inc., NewYork, N.Y., 1988; Handbook of Heterocyclic Chemistry, Katritzky andPozharskii, 2^(nd) Ed., Pergamon, New York, N.Y., 2000 and referencescited therein. The starting materials for the present compounds may beprepared using standard synthetic transformations of chemical precursorsthat are readily available from commercial sources, including AldrichChemical Co. (Milwaukee, Wis.); Sigma Chemical Co. (St. Louis, Mo.);Lancaster Synthesis (Windham, N.H.); Ryan Scientific (Columbia, S.C.);Maybridge (Cornwall, UK); Matrix Scientific (Columbia, S.C.); Arcos,(Pittsburgh, Pa.) and Trans World Chemicals (Rockville, Md.).

The procedures described herein for synthesizing the compounds mayinclude one or more steps of protecting group manipulations and ofpurification, such as, recrystallization, distillation, columnchromatography, flash chromatography, thin-layer chromatography (TLC),radial chromatography and high-pressure chromatography (HPLC). Theproducts can be characterized using various techniques well known in thechemical arts, including proton and carbon-13 nuclear magnetic resonance(¹H and ¹³C NMR), infrared and ultraviolet spectroscopy (IR and UV),X-ray crystallography, elemental analysis and HPLC and mass spectrometry(LC-MS). Methods of protecting group manipulation, purification,structure identification and quantification are well known to oneskilled in the art of chemical synthesis.

Appropriate solvents are those which will at least partially dissolveone or all of the reactants and will not adversely interact with eitherthe reactants or the product. Suitable solvents are aromatichydrocarbons (e.g, toluene, xylenes), halogenated solvents (e.g,methylene chloride, chloroform, carbontetrachloride, chlorobenzenes),ethers (e.g, diethyl ether, diisopropylether, tert-butyl methyl ether,diglyme, tetrahydrofuran, dioxane, anisole), nitrites (e.g,acetonitrile, propionitrile), ketones (e.g, 2-butanone, dithyl ketone,tert-butyl methyl ketone), alcohols (e.g, methanol, ethanol, n-propanol,iso-propanol, n-butanol, t-butanol), dimethyl formamide (DMF),dimethylsulfoxide (DMSO) and water. Mixtures of two or more solvents canalso be used. Suitable bases are, generally, alkali metal hydroxides,alkaline earth metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, barium hydroxide, and calcium hydroxide;alkali metal hydrides and alkaline earth metal hydrides such as lithiumhydride, sodium hydride, potassium hydride and calcium hydride; alkalimetal amides such as lithium amide, sodium amide and potassium amide;alkali metal carbonates and alkaline earth metal carbonates such aslithium carbonate, sodium carbonate, Cesium carbonate, sodium hydrogencarbonate, and cesium hydrogen carbonate; alkali metal alkoxides andalkaline earth metal alkoxides such as sodium methoxide, sodiumethoxide, potassium tert-butoxide and magnesium ethoxide; alkali metalalkyls such as methyllithium, n-butyllithium, sec-butyllithium,t-bultyllithium, phenyllithium, alkyl magnesium halides, organic basessuch as trimethylamine, triethylamine, triisopropylamine,N,N-diisopropylethylamine, piperidine, N-methyl piperidine, morpholine,N-methyl morpholine, pyridine, collidines, lutidines, and4-dimethylaminopyridine; and bicyclic amines such as DBU and DABCO.

As described previously, in preparing the compositions for oral dosageform, any of the usual pharmaceutical media can be employed. Forexample, in the case of oral liquid preparations such as suspensions,elixirs and solutions, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like may be used; or in the caseof oral solid preparations such as powders, capsules and tablets,carriers such as starches, sugars, microcrystalline cellulose, diluents,granulating agents, lubricants, binders, disintegrating agents, and thelike may be included. Because of their ease of administration, tabletsand capsules represent the most advantageous oral dosage unit form inwhich solid pharmaceutical carriers are employed. If desired, tabletsmay be coated by standard aqueous or nonaqueous techniques. In additionto the common dosage forms set out above, controlled release meansand/or delivery devices may also be used in administering the instantcompounds and compositions.

It is understood that the functional groups present in compoundsdescribed in the Schemes below can be further manipulated, whenappropriate, using the standard functional group transformationtechniques available to those skilled in the art, to provide desiredcompounds described in this invention.

Other variations or modifications, which will be obvious to thoseskilled in the art, are within the scope and teachings of thisinvention. This invention is not to be limited except as set forth inthe following claims.

Pyrazinone compounds of the present invention can be prepared asoutlined in the following Schemes and Examples. Alternatively, theinstant compounds can be prepared by adapting the methods described byTaylor, Takahashi and Kobayshi (Heterocycles 1996, 43(2), 437-442), andBeccallie and Marchesini (Synthesis, 1991, 861-862).

An appropriate bromo or iodo acetophenone 1 can be oxidized with SeO₂using the conditions described by Sakamoto, T. et al. [Chem Pharm. Bull.28: 571-577(1980)] to provide the corresponding carboxylic acid, whichwithout isolation can then be converted into the correspondingα-ketoester 2. Reaction of 2 with an appropriate diamine 3, optionallyfollowed by capping of the NH group through N-alkylation, can provide aregioisomeric mixture of pyrazinones 4 and 5. Separation of theregioisomers 4 and 5 by chromatography, followed by a Pd-catalyzedcross-coupling Suzuki reaction [Huff, B. et al., Org. Synth. 75: 53-60(1997); Goodson, F. E. et al. Org. Synth. 75: 61-68 (1997)] of theseindividual isomers with an appropriately substituted aryl boronic acid 6provides biphenyl pyrazinones 7 and 9. When R¹ in 7 is a carboxylic acidester (R¹═COOR), it can be hydrolyzed to provide the correspondingcarboxylic acid (R¹═COOH), which can be then treated with an appropriateamine R^(a)—NH—R^(b) in the presence of an appropriate carboxylic acidactivating agent, such as carbonyl-di-imidazole (CDI) to provide theamide 8. Alternatively, the ester 7 can be treated with excess ammoniain a polar solvent, such as methanol, to provide the correspondingprimary amide 8 (where R^(a)═R^(b)═H). The pyrazinone regioisomer 9 alsocan be converted into appropriate amide derivatives employing thechemistry described above.

In an alternative approach to Scheme 1, the boronic acid 6 can becoupled with an appropriately substituted 3-iodo bromobenzene 10 toprovide the biphenyl 11, which can be then treated with n-BuLi followedby diethyloxalate to provide the α-ketoester 12. Reaction of 12 with anappropriate diamine 3 followed by acid hydrolysis and amidation, asshown in Scheme 1, provides a mixture of pyrazinone amides 13 and 14.Separation of the regioisomers 13 and 14 followed by treatment withTMSCHN₂ provides the N-methyl pyrazinones 15 and 16.

The pyrazinones 13 and 14 can be also alkylated with other appropriatealkylating agents to provide pyrazinones 17 and 18.

In another approach, as described in Scheme 4, an appropriatelysubstituted ketoester 2 can be condensed with methyl diaminopropionate(19) to provide the pyrazinone acid 20, which can be condensed with anappropriate aryl boronic acid 6 to provide the corresponding biphenylpyrazinone carboxylic acid 21. The pyrazinone carboxamides 22 and 23 canbe prepared from the carboxylic acid 21 as described in Scheme 4.

The pyrazinone carboxylic acid 21 can also be synthesized using analternative approach outlined in Scheme 5. The aryl halide (or triflate)24 can be coupled with an appropriately substituted aryl boronic acid 25under Suzuki conditions to provide the corresponding biphenyl methylketone 26, which can be oxidized to produce the desired ketoester 12.

Appropriate solvents are those which will at least partially dissolveone or all of the reactants and will not adversely interact with eitherthe reactants or the product. Suitable solvents include aromatichydrocarbons (e.g, toluene, xylenes), halogenated solvents (e.g,methylene chloride, chloroform, carbontetrachloride, chlorobenzenes),ethers (e.g, diethyl ether, diisopropylether, tert-butyl methyl ether,diglyme, tetrahydrofuran, dioxane, anisole), nitriles (e.g,acetonitrile, propionitrile), ketones (e.g, 2-butanone, diethyl ketone,tert-butyl methyl ketone), alcohols (e.g, methanol, ethanol, n-propanol,iso-propanol, n-butanol, t-butanol), dimethyl formamide (DMF),dimethylsulfoxide (DMSO) and water. Mixtures of two or more solvents canalso be used. Suitable bases include alkali metal hydroxides, alkalineearth metal hydroxides such as lithium hydroxide, sodium hydroxide,potassium hydroxide, barium hydroxide, and calcium hydroxide; alkalimetal hydrides and alkaline earth metal hydrides such as lithiumhydride, sodium hydride, potassium hydride and calcium hydride; alkalimetal amides such as lithium amide, sodium amide and potassium amide;alkali metal carbonates and alkaline earth metal carbonates such aslithium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, and cesium hydrogen carbonate; alkali metal alkoxides andalkaline earth metal alkoxides such as sodium methoxide, sodiumethoxide, potassium tert-butoxide and magnesium ethoxide; alkali metalalkyls such as methyllithium, n-butyllithium, sec-butyllithium,t-bultyllithium, phenyllithium, alkyl magnesium halides, organic basessuch as trimethylamine, triethylamine, triisopropylamine,N,N-diisopropylethylamine, piperidine, N-methyl piperidine, morpholine,N-methyl morpholine, pyridine, collidines, lutidines, and4-dimethylaminopyridine; and bicyclic amines such as DBU and DABCO.

EXAMPLE 1

Step 1: Preparation of

A 100-ml round-bottom flask fitted with a stirbar, condenser, and septumwas flushed with N₂ and charged with 3-bromoacetophenone (2.50 g) andanhydrous pyridine (20 mL), followed by selenium dioxide (2.8 g). Thereaction mixture was heated to 100° C. After one hour, the reaction wascooled to room temperature and pyridine was distilled off under reducedpressure. The resulting thick oil was partitioned between 50 ml 1N KCland 50 ml EtOAc. The aqueous phase was extracted once more with 50 mlEtOAc, and the combined organic phase was dried over sodium sulfate andconcentrated in vacuo. The resulting crude acid was azeotroped with 10ml of anhydrous toluene.

To a 100-ml round-bottom flask containing the crude acid were addedanhydrous DMF (20 ml), Cs₂CO₃ (4.11 g), and methyl iodide (3.58 g)sequentially. The mixture was heated at 40 ° C. for 1 hour under N₂,cooled to room temperature, diluted with 200 ml saturated NH₄Clsolution, and extracted two times with 200 ml EtOAc/hexanes (1/1). Thecombined organic phase was dried over Na₂SO₄, concentrated in vacuo, andpurified by column chromatography on silica gel (25% EtOAc/hexanes) toprovide the desired product.

¹H NMR (CDCl₃): 8.22 (s, 1H), 8.01 (d, J=8 Hz, 1H), 7.83 (d, J=8 Hz,1H), 4.0 (s, 3H)

MS: m/e 243/245 (M+1)⁺

Step 2: Preparation of

A 50-ml round-bottom flask fitted with a stirbar and septum was flushedwith N₂ and charged with the keto methyl ester from Step 1 (0.500 g),anhydrous methanol (10 mL), and methyl 2,3-diaminopropionate (0.772 g)[prepared from 2,3-diaminopropionic acid, commercially available fromSigma-Aldrich]. To the resulting mixture (a white suspension) was addedsodium methoxide solution (3.4 ml, 25% w/w) dropwise over 5 min. Theyellow reaction mixture thus obtained was stirred at room temperatureunder air for 30 min before being concentrated in vacuo. The resultingyellow solid was acidified with 50 ml 1N HCl solution and extracted (2times) with 50 ml EtOAc. The combined organic phase was dried oversodium sulfate and concentrated under reduced pressure. The crudepyrazinone carboxylic acid thus obtained was dried under vacuum and thencarried onto the next reaction.

To a solution of the crude pyrazinone carboxylic acid in anhydrous DMF(5 ml) were added Cs₂CO₃ (0.652 g), and methyl iodide (0.568 g)sequentially, and the mixture was heated to 40° C. for 1 hour. Thereaction was then cooled to room temperature, diluted with 50 mlsaturated NH₄Cl solution, and extracted (2 times) with 50 ml EtOAc. Thecombined organic phase was dried over Na₂SO₄ and concentrated in vacuoto give a regioisomeric mixture of N-methyl pyrazinone. The isomers wereseparated by column chromatography using silica gel (50-75%EtOAc/hexanes) to give regioisomer 1 N-methyl pyrazinone methyl ester.

¹H NMR (CDCl₃): 8.54 (t, J=2 Hz, 1H), 8.34 (d, J=8 Hz, 1H), 8.20 (s,1H), 7.60 (d, J=8 Hz, 1H), 7.34 (t, J=8 Hz, 1H), 3.98 (s, 3H), 3.69 (s,3H)

MS: m/e 323/325 (M+1)⁺

regioisomer 2: ¹H NMR (CDCl₃): 8.57 (t, J=2 Hz, 1H), 8.38 (d, J=8 Hz,1H), 8.04 (s, 1H), 7.60 (d, J=8 Hz, 1H), 7.34 (t, J=8 Hz, 1H), 3.96 (s,3H), 3.62 (s, 3H)

MS: m/e 323/325 (M+1)⁺

Step 3: 2-(Trifluoromethoxy)phenylboronic acid

n-Butyllithium (5.9 ml, 9.5 mmol) was added to a solution of1-bromo-2-(trifluoromethoxy)benzene (2 g, 8.2 mmol) in tetrahydrofuran(28 ml) at −78° C. and stirred for 45 minutes. Triisopropyl borate (2.58ml, 11.1 mmol) was added dropwise to the reaction mixture and thesolution was slowly brought to room temperature over 16 hours. Thereaction mixture was quenched with water, made basic with 2N NaOH andextracted with ethyl acetate. The aqueous solution was acidified with 2NHCl, stirred for 1 hour at room temperature and extracted into ethylacetate. The organic layer was washed with water, brine solution anddried over sodium sulfate. It was filtered and concentrated to give theproduct (1.10 g, 65%) as a white solid.

¹HNMR (CDCl₃) (δ, ppm): 7.96 (dd, J=7.2, 1.6 Hz, 1 H), 7.53 (ddd, J=9.1,7.3, 1.8 Hz, 1 H), 7.38 (td, J=7.3, 0.7 Hz, 1 H), 7.28 (d, J=8.2 Hz, 1H), 5.25 (br s, 2H). MS (M+H): 206.9.

Step 4: Preparation of

A 10-ml round-bottom flask with a stirbar was charged with aryl bromidefrom Step 2 (0.08 g) and 2-(trifluoromethoxy)phenyl boronic acid fromStep 3 (0.153 g), followed by KF (0.086 g), and anhydrous dioxane (1ml). Then Pd(OAc)₂ (0.011 g) and 2-(dicyclohexylphosphino)biphenyl(0.035 g) were added sequentially and the mixture was heated to 100° C.for 2 hours. After being cooled to room temperature, the mixture wasdiluted with 10 ml saturated NH₄Cl and extracted with 10 mlEtOAc/hexanes (1/1) twice. The combined organic phase was dried overNa₂SO₄ and concentrated. The crude mixture was purified by columnchromatography on silica gel (50% EtOAc/hexanes) to give pure desiredbiphenyl pyrazinone compound.

The methyl ester obtained above was placed in a thick-wall 25-ml tubewith a stirbar, and 1 ml of a 2M solution of ammonia in methyl alcoholwas then added. The tube was cooled to −78° C. in a dry-ice bath andfurther charged with liquid ammonia (˜1 ml). The tube, after sealing itwith a Teflon stopcock, was heated to 40° C. for 12 hours and thencooled to room temperature. The solvent and the excess reagent wereremoved by slow evaporation under reduced pressure. The off-white solidobtained was purified via reversed-phase HPLC (10-90% CH₃CN/H₂O) to givethe desired pyrazinone amide.

¹H NMR (CDCl₃): 8.42 (t, J=1.5 Hz, 1H), 8.37 (d, J=8 Hz, 1H), 8.25 (s,1H), 7.61 (d, J=8 Hz, 1), 7.58 (d, J=7.5 Hz, 1H), 7.54 (m, 1H),7.48-7.40 (m, 3H), 3.70 (s, 3H)

MS: m/e 390 (M+1)⁺

EXAMPLE 2

Step 1: Preparation of:

A 25-ml round-bottom flask with a stirbar was charged1-bromo-3-iodobenzene (1.01 g) and 2-(trifluoromethyl)phenylboronic acid(0.580 g), followed by aq.2M Na₂CO₃ (3 ml), toluene (10 ml) andPd(Ph₃P)₄ (0.139 g). The mixture was heated at 100° C. for 2 hours, thencooled to room temperature, diluted with 30 ml saturated NH₄Cl andextracted with 30 ml hexanes (2 times). The combined organic phase wasdried over Na₂SO₄ and concentrated in vacuo. The crude mixture waspurified by column chromatography on silica gel (using hexanes) to givethe desired biphenyl bromide as an oil.

¹H NMR (CDCl₃): 7.80 (d, J=8 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 7.58 (m,1H), 7.55-7.52 (m, 2H), 7.36 (d, J=8 Hz, 1H), 7.32 (m, 2H)

MS (ESI): m/e 301/303 (M+1)⁺

Step 2: Preparation of:

To a solution of the biphenyl bromide from Step 1 above (0.600 g) inanhydrous THF (5 ml) at −78° C. was added a 1.6M solution of nBuLi inhexanes (1.42 ml) dropwise in 5 min. The resulting bright yellowsolution, after stirring at −78° C. for 15 min, was cannulated intoanother flask containing a pre-cooled (−78° C.) solution of diethyloxalate (0.907 g) in anhydrous THF (5 ml). After stirring for 30 min at−78° C., the reaction was quenched with 30 ml of saturated NH₄Cl, andextracted two times with 20 ml EtOAc/hexanes (1/1). The combined organicphase was dried over Na₂SO₄ and concentrated in vacuo. The crude mixturewas purified by column chromatography using silica gel (15%EtOAc/hexanes) to give the desired keto ester.

¹H NMR (CDCl₃): 8.10 (d, J=8 Hz, 1H), 8.09 (s, 1H), 7.81 (d, J=8 Hz,1H), 7.66-7.60 (m, 4H), 7.36 (d, J=8 Hz, 1H), 4.47 (q, J=7.5 Hz, 2H),1.42 (t, J=7.5 Hz, 3H)

MS (ESI): m/e 323 (M+1)⁺

Step 3: Preparation of

To a solution of the keto ester from Step 2 above (0.410 g) in anhydrousmethanol (6 ml) was added methyl-2,3-diamino propionate (0.525 g) atambient temperature, giving rise to a white suspension. After 15 min ofstirring, a solution of NaOMe (2.35 ml, 25% w/w) was added slowly over 5min. The resulting yellow reaction was stirred at room temperature underair for 30 min before being concentrated under reduced pressure. Thesolid obtained was treated with 1N HCl (40 ml) and extracted with EtOAc( 2×40 ml). The combined organic phase was dried over sodium sulfate,concentrated and dried in vacuo. The crude pyrazinone carboxylicacidthus obtained was carried onto the next reaction described below.

A 50-ml round-bottom flask equipped with a stirbar and septum wascharged with the crude acid (from above) and anhydrous DMF (4 ml) underN₂. 1,1′-carbonyl diimidazole (0.437 g) was added, and the mixture washeated at 40° C. for 15 min. NH₄OAc (0.406 g) was then introduced in oneportion and the mixture was stirred at room temperature overnight. Thereaction was diluted with 50 ml saturated NH₄Cl solution, and extracted(2 times) with 50 ml EtOAc. The combined organic phase was dried overNa₂SO₄, concentrated in vacuo, and purified by column chromatography onsilica gel (EtOAc) to give the desired pyrazinone amide.

¹H NMR (CD₃OD): 6.91 (d, J=8 Hz, 1H), 6.85 (s, 1H), 6.52 (s, 1H), 6.40(s, 3H), 6.26 (d, J=8 Hz, 1H), 6.11 (t, J=8 Hz, 1H), 6.03 (t, J=8 Hz,1H), 5.97 (t, J=8 Hz, 1H), 5.89 (t, J=8.5 Hz, 1H)

MS: m/e 360 (M+1)⁺

Step 4: Preparation of:

To a solution of the amide (from Step 3) (0.268 g) in diethyl ether (2ml) and methyl alcohol (2 ml) was added 0.75 ml of 2M solution ofTMSCHN₂ in hexanes at 0° C. The resulting yellow mixture was stirred at0° C. for 1 hour and concentrated in vacuo. The crude product waspurified by reversed-phase HPLC (10-90% CH₃CN/H₂O) to give the desiredN-methylated product.

¹H NMR (CDCl₃): 8.34 (d, J=7.5 Hz, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 7.75(d, J=8 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 7.51-7.47 (m, 2H), 7.44 (d,J=7.5 Hz, 1H), 7.38 (d, J=8 Hz, 1H), 7.29 (s, 1H)

MS (ESI): m/e 374 (M+1)⁺.

Other Examples of the instant invention are provided below.

TABLE 1

Example (m/e) # R⁶ R³ R² R¹ (M + H) 3 —OCF₃ H H —CONH₂ 376 4 —OCF₃ CH₃ H—COOH 377 5 —OCF₃ CH₃ —CONH₂ H 390 6 —CF₃ CH₃ —CONH₂ H 374 7 —CF₃ H H—COO-t-Bu 417 8 —CF₃ H H —CONH-t-Bu 416 9 —CF₃ H H —COOH 361 10—OCH₂CF₂CF₃ H H —CONH₂ 440 11 —OCH₂CF₂CF₃ H H —COOH 441 12 —OCH₂CF₃ H H—CONH₂ 390 13 —OCH₂CF₃ CH₃ H —CONH₂ 404 14 —OCH₂CF₃ H —CONH₂ H 390 15—OCH₂CF₃ CH₃ —CONH₂ H 404 16 —OCH₂CF₂CF₃ CH₃ H —CONH₂ 454 17 —OCH₂CF₃ HH —COOH 391 18 —CF₃ —CH₂CF₃ H —CONH₂ 442 19 —CF₃ —C(CH₃)₃ H —CONH₂ 41620 —CF₃ —CH(CH₃)₂ H —CONH₂ 402 21 —CF₃ —CH₂CH₃ H —CONH₂ 388 22 —OCF₃ CH₃—CONH₂ —CONH₂ 432

TABLE 2

Example (m/e) # R⁷ R⁶ R³ R² R¹ (M + H) 23 4-CF₃ —CF₃ —CH₃ H —CONH₂ 44224 4-CF₃ —CF₃ —CH₃ —CONH₂ H 442 25 5-F —OCF₃ —CH₃ H —CONH₂ 408 26 5-CF₃—OCF₃ —CH₃ H —CONH₂ 458 27 5-F —OCF₃ H H —CONH₂ 394 28 5-F —OCH₂CF₂CF₃ HH —CONH₂ 458 29 5-F —OCH₂CF₃ H H —CONH₂ 408 30 5-F —OCH₂CF₂CF₃ —CH₃ H—CONH₂ 472 31 5-F —OCH₂CF₃ —CH₃ H —CONH₂ 422 32 6-F —CF₃ H H —CONH₂ 37833 3-F —CF₃ H H —CONH₂ 378 34 6-F —CF₃ —CH₃ H —CONH₂ 392 35 3-F —CF₃—CH₃ H —CONH₂ 392 36 5-F —CF₃ —CH₃ H —CONH₂ 392 37 4-F —CF₃ —CH₃ H—CONH₂ 392 38 4-F —CF₃ H H —CONH₂ 378 39 5-F —CF₃ H H —CONH₂ 378 405-CH₃ —CF₃ —CH₃ H —CONH₂ 388 41 4-CH₃ —CF₃ —CH₃ H —CONH₂ 388

TABLE 3

Example (m/e) # R⁷ R⁶ R⁵ R⁴ R³ R² R¹ (M + H) 42 H —OCF₃ F H —CH₃ —CONH₂H 408 43 H —OCF₃ F H —CH₃ H —CONH₂ 408 44 H —OCF₃ H F —CH₃ H H 365 45 H—OCF₃ H F —CH₃ H —CONH₂ 408 46 H —OCH₂CF₃ H F —CH₃ H —CONH₂ 422 47 H—OCF₃ H F —CH₃ H —COOH 409 48 5-F —OCF₃ F H —CH₃ H —CONH₂ 426 49 5-F—OCF₃ H F —CH₃ H —CONH₂ 426 50 H —CF₃ H F —CH₃ H —CONH₂ 392 51 H —CF₃ FH —CH₃ H —CONH₂ 392 52 H —OCF₃ H F H H —CONH₂ 394 53 H —OCF₃ F H H H—CONH₂ 394 54 5-F —OCF₃ F H H H —CONH₂ 412 55 H —CF₃ F H —CH₃ H —COOH393 56 5-F —OCH₂CF₂CF₃ F H —CH₃ H —CONH₂ 490 57 H —CF₃ H F —CH₃ H —COOH393 58 H —OCF₃ F H —CH₃ H —COOCH₃ 423 59 H —CF₃ F H —CH₃ H —COOCH₃ 40760 H —CF₃ F H —CH₃ H —COOCH₃ 353 61 5-F —OCH₂CH₃ F H —CH₃ H —COOCH₃ 40162 5-F —OCH₂CF₃ F H —CH₃ H —COOCH₃ 455 63 H —OCF₃ F H H H —COOH 395 64 H—OCF₃ H F H H —COOH 395 65 5-F —OCH₂CF₂CF₃ F H —CH₃ H —COOH 491 66 H—CF₃ H F H H —CONH₂ 378 67 H —CF₃ Br H —CH₃ H —COOCH₃ 453 68 H —CF₃ F HH H —CONH₂ 378 69 H —CF₃ Br H —CH₃ H —CONH₂ 452 70 5-F —CF₃ H F —CH₃ H—CONH₂ 410 71 H —CF₃ Br H H H —COOCH₃ 439 72 H —CF₃ Br H H H —COOH 42573 5-F —OCH₂CF₃ F H H H —CONH₂ 426 74 3-F —CF₃ F H —CH₃ H —CONH₂ 410 753-F —CF₃ H F —CH₃ H —CONH₂ 410 76 5-F —CF₃ F H —CH₃ H —CONH₂ 410 77 4-F—CF₃ F H —CH₃ H —CONH₂ 410 78 4-F —CF₃ H F H H —CONH₂ 396

TABLE 4

Example (m/e) # R⁷ R⁶ R⁴ R³ R² R¹ (M + H) 79 H —OCF₃ F —CH₃ H —CONH₂ 40880 H —OCF₃ F —CH₃ —CONH₂ H 408 81 H —OCF₃ F —CH₃ H —COOH 409 82 H —OCF₃F H H —CONH₂ 394 83 H —OCF₃ F H H —COOH 395 84 H —CF₃ F —CH₃ H —CONH₂392 85 H —CF₃ F —CH₃ H —COOH 393 86 5-F —OCH₂CF₂CF₃ F —CH₃ H —CONH₂ 49087 5-F —OCH₂CF₃ F —CH₃ H —CONH₂ 440 88 H —OCF₃ F —CH₃ H —COOCH3 423 895-F —CF₃ F —CH₃ H —CONH₂ 410 90 H —CF₃ F H H —CONH₂ 378 91 3-F —CF₃ F—CH₃ H —CONH₂ 410

TABLE 5

Example (m/e) # R⁷ R⁶ R⁵ R⁴ R³ R² R¹ (M + H) 92 H OCF₃ H H CH₂CONH₂ HCONH₂ 433 93 H CF₃ H H CH₂CONH₂ H CONH₂ 417 94 H OCF₃ H H CH₂COOH HCONH₂ 434 95 H OCF₃ H H CH₂COO-tBu H CONH₂ 489 96 H OCF₃ H H CH₂CN HCONH₂ 415 97 H CF₃ H H CH₂CN H CONH₂ 399 98 H CF₃ H H CH₂COOH H CONH₂418 99 H CF₃ H H CH₂COO-tBu H CONH₂ 474 100 H OCF₃ H H

H CONH₂ 457 101 H CF₃ H H

H CONH₂ 441 102 H CF₃ H H

H CONH₂ 442 103 H OCF₃ H H

H CONH₂ 458 104 H OCF₃ H H CH₂CH₂OH H CONH₂ 420 105 H CF₃ H H CH₂CH₂OH HCONH₂ 404 106 H OCF₃ H H CH₂CH₂NH₂ H CONH₂ 419 107 H CF₃ H H CH₂CH₂NH₂ HCONH₂ 403 108 H OCF₃ H H CH₂CH₂N(CH₃)₂ H CONH₂ 447 109 H CF₃ H HCH₂CH₂N(CH₃)₂ H CONH₂ 431 110 4-F CF₃ H H CH₂CONH₂ H CONH₂ 451 111 5-FCF₃ H H CH₂CONH₂ H CONH₂ 451 112 H CF₃ F H CH₂CONH₂ H CONH₂ 451 113 HCF₃ F H CH₂CONH₂ H CONH₂ 451 114 4-F CF₃ F H CH₂CONH₂ H CONH₂ 469 1155-F CF₃ F H CH₂CONH₂ H CONH₂ 469

EXAMPLE 116

To a solution of the amide (Example 32) (0.060 g) in DMF (1 mL), wasadded chloroacetone (0.029 g) and potassium carbonate (0.043 g). Theresulting mixture was stirred at 40° C. for 40 minutes, and then dilutedwith 10 mL saturated NH₄Cl solution and extracted twice with 20 mLEtOAc/hexanes (1/1). The combined organic phase was dried over Na₂SO₄,concentrated in vacuo, and purified to give the desired methyl ketone.

¹H NMR (CD₃OD): 8.47 (m, 1H), 8.36 (s, 1H), 8.20 (s, 1H), 7.67 (m, 1H),7.63 (m, 1H), 7.50 (m, 1H), 7.41 (m, 1H), 5.13 (s, 2H), 2.15 (s, 3H).

MS: m/e 434 (M+1)⁺.

EXAMPLE 117

Step 1: Preparation of

To the solution of 3-(trifluoromethoxyl)fluorobenzene (1 g, 5.5 mmol) in10 mL THF at −78° C., n-BuLi (1.6M, 3.75 mL) was added dropwise. Theresulting solution was stirred at −78° C. for 30 min. I₂ (2.1 g, 8.25mmol) in THF (5 mL) was added. The mixture was warmed to roomtemperature and then quenched with Na₂CO₃ in saturated Na₂S₂O₃ (1:10)(30 mL). The crude product was extracted with ether. The ether layer wasdried over Na₂SO₄ and filtered through a short silica gel column to givethe desired iodide as an oil.

¹H NMR (CDCl₃): 7.39 (m, 1H), 7.12 (d, J=9.0 Hz, 1H), 7.05 (t, J=6.0 Hz,1H)

MS (ESI): m/e 307 (M+1)⁺

Step 2: Preparation of

To a solution of the aryl iodide (1.4 g) (from Step 1 above) inanhydrous dioxane (20 mL) were added 3-acetylphenylboronic acid (2.5 g)and KF (0.87 g) followed by Pd(dppf)₂Cl₂ (376 mg). The mixture washeated to 90° C. for 2 h. After cooling to room temperature, the mixturewas filtered through a pad of celite, washed with EtOAc. The filtratewas concentrated in vacuo, and the crude product, thus obtained, waspurified by column chromatography on silica gel using 10% ether inhexane to give the desired product as an oil.

¹H NMR (CDCl₃): 8.05 (m, J=8 Hz, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 7.60(s, 1H), 7.42 (m, 1H), 7.22 (d, J=12 Hz, 1H), 7.20 (m, 1H)

MS (ESI): m/e 299 (M+1)⁺

Step 3: Preparation of

To a solution of biphenyl acetophenone (2.8 g) (from last Step 2) in drypyridine (40 mL), Selenium dioxide (2.1 g) was added, and the mixturewas heated at 10° C. for 2 h. The precipitated Selenium (black) wasfiltered off, and the filterate was concentrated under reduced pressure.The residue obtained was treated with 10% NaOH and extracted with ether.The aqueous layer was acidified and extracted with EtOAc. The organicphase was dried over Na₂SO₄ and concentrated in vacuo to give desiredproduct as a solid.

¹H NMR (CDCl₃): 8.46 (d, J=8 Hz, 1H), 8.41 (s, 1H), 7.75 (d, J=8 Hz,1H), 7.67 (t, J=15 Hz, 1 H), 7.45 (m, 1H), 7.25 (d, J=7 Hz, 1H), 7.21(t, J=18 Hz, 1H).

MS (ESI): m/e 329 (M+1)⁺

Step 4: Preparation of

To a solution of the keto-acid (2 g) (from Step 3) in DMF (50 mL) wereadded dimethyl sulfate (1.5 g) and K₂CO₃ (3.3 g). The mixture wasstirred at 50° C. for 2 h. The solvent was removed under reducedpressure, and the residue obtained was dissolved in EtOAc, washed with1N HCl, dried over Na₂SO₄ and purified by column chromatography onsilica gel.

¹H NMR (CDCl₃): 8.12 (d, J=8 Hz, 1H), 8.09 (s, 1H), 7.72 (d, J=9 Hz,1H), 7.63 (t, J=15 Hz, 1 H), 7.45 (m, 1H), 7.24 (d, J=7 Hz, 1H), 7.19(t, J=18 Hz, 1H)

MS (ESI): m/e 343 (M+1)⁺

Step 5: Preparation of

To a solution of the keto-ester (1.5 g) (from Step 4) in MeOH (10 mL)was added methyl-2,3-diamino propionate (1.2 g) followed by 40% NaOMe(5.7 mL). The mixture was stirred at room temperature for 2 h, thenacidified with concentrated. After stirring at room temperatureovernight, the solvent was removed under reduced pressure. The residueobtained was then dissolved in 10% KOH, washed with ether and acidifiedwith HCl. The mixture was extracted with EtOAc to give the crude productwhich was purified by reversed-phase chromatography to give 1.2 g of thefinal pyrazinone carboxylic acid.

¹H NMR (CD₃OD): 8.49 (d, J=9 Hz, 1H), 8.46 (s, 1H), 8.07 (s, 1H), 7.59(t, J=16 Hz, 1 H), 7.47-7.54 (m, 2H), 7.26-7.32 (m, 2H).

MS (ESI): m/e 395 (M+1)⁺

EXAMPLE 118

To a solution of the pyrazinone carboxylic acid (1.2 g) (from Step 5 ofExample 117) in anhydrous DMF (10 mL) was added 1,1′-carbonyldiimidazole (1.4 g). The mixture was heated at 40° C. for 15 min, andanhydrous NH₄OAc (1.5 g) was then introduced in one portion to thereaction. The mixture was stirred at room temperature overnight, thendiluted with saturated NH₄Cl solution (50 mL), and extracted (2×) withEtOAc. The combined organic phase was dried over Na₂SO₄, concentrated invacuo, and purified by reversed-phase chromatography.

¹H NMR (CD₃OD): 8.49 (d, J=9 Hz, 1H), 8.46 (s, 1H), 8.07 (s, 1H), 7.59(t, J=16 Hz, 1 H), 7.47-7.54 (m, 2H), 7.26-7.32 (m, 2H).

MS (ESI): m/e 394 (M+1)⁺

EXAMPLE 119

To a solution of the amide (100 mg) (from Example 118) in dry DMF (2 mL)were added, K₂CO₃ (36 mg) and 2-iodoethanol (90 mg). The reactionmixture was heated at 50° C. for 2 h, then cooled to room temperatureand concentrated in vacuo. The residue was dissolved in EtOAc, washedwith 1N HCl, dried over Na₂SO₄ and concentrated in vacu. The crudeproduct obtained was purified by column chromatography using silica gel(1:2 acetone to ethyl acetate) to give the desired product as whitesolid.

¹H NMR (CD₃OD): 8.46 (d, J=8 Hz, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 7.50(t, J=16 Hz, 1 H), 7.48-7.58 (m, 2H), 7.27-7.34 (m, 2H).

MS (ESI): m/e 438 (M+1)⁺

EXAMPLE 120

Step 1: Preparation of 3,4-difluoro-6-(trifluoromethoxyl)benzyl bromide

To a cold (0° C.) solution of 2-bromo-4,5-difluorophenol (5 g, 24 mmol)and N-methyl morpholine (5.3 mL, 48 mmol) in dry THF (20 mL) was addedphenyl chlorodithioformate (3.4 mL, 24 mmol). The resulting solution wasstirred at room temperature for one hour. After removal of the solvent,the residue was dissolved in ether and washed with water and brine. Theether layer was then dried over anhydrous sodium sulfate. Afterconcentration, the crude product was purified via column chromatographyon silica gel to afford the thiocarbonate as a white solid, 8.5 g, 99%yield. This thiocarbonate was then dissolved in dichloromethane in aplastic bottle. At −78° C., HF-pyridine was added, followed by smallportions of dibromohydentoin. The reaction mixture was allowed to warmup to room temperature over 2 hours. After another 2 hours stirring atroom temperature, the reaction was quenched with 2N NaOH aqueous andextracted with ether. The organic layer was separated and washed withwater and brine. The ether layer was then dried over anhydrous sodiumsulfate. After concentration, the crude product was applied to columnchromatography on silica gel to afford the final product as colorlessoil, 6.0 g, 92% yield. This product was used in Step 2 below.

Step 2: Preparation of 3,4-difluoro-6-trifluoromethoxyl)benzyl boronicacid

To the solution of 3,4-difluoro-6-(trifluoromethoxyl)phenyl bromide (2g, 7.2 mmol) in dry THF (20 mL) was added isopropylmagnesiumchloride(5.4 mL, 2M in THF, 11 mmol). The reaction mixture was stirred at roomtemperature for 6 hours before it was quenched with triisopropyl borate(2 g, 11 mmol). The resulting mixture was stirred at room temperaturefor 14 hours. Finally this reaction was treated with 2N HCl and wasstirred for 3 hours. The organic layer was separated and the aqueouslayer was extracted with ethyl acetate. The combined organic layer waswashed with water and brine, and dried over anhydrous sodium sulfate.After concentration, the crude product was dissolved in 2N NaOH andwashed with ether (once). The aqueous layer was then acidified to pH ˜1and extracted with ethyl acetate. After concentration, the product wascollected as an off-white solid.

¹H NMR (CDCl₃) (δ, ppm): 7.76 (t, J=19 Hz, 1H), 7.15 (dd, J=12, 19 Hz,1H), 5.08 (bs, 2H).

MS (ESI): m/e 243 (M+1)⁺

Step 3: Preparation of

To the solution of 3,4-difluoro-6-(trifluoromethoxyl)benzyl boronic acid(from Step 2 above) (263 mg, 1.1 mmol),1-(3′-bromobenzene)-3-carboxylpyrazinone (from Step 1, Example 250) (200mg, 0.68 mmol), and Na₂CO₃ (2N, 4 mL) in ethanol (4 ml), under N₂, wasadded Pd(dppf)Cl₂ (56 mg, 0.01 mmol). The resulting yellow suspensionwas stirred at 90° C. for 6 hours. After cooling to room temperature,the solvent was removed under reduced pressure. The residue waspartitioned between ethyl acetate and 2N HCl. The aqueous layer wasextracted with ethyl acetate. The combined organic layer was washed withbrine and dried over anhydrous sodium sulfate. After concentration, theproduct was dried on a high vacuum pump and used in Step 4.

Step 4: Preparation of

The crude acid from Step 3 above was dissolved in dry DMF and treatedwith carbonyldiimidazole (165 mg, 1.0 mmol). The reaction was stirred at55° C. for 2 hours before the addition of ammonium acetate (250 mg,excess). After stirring at room temperature for overnight, the reactionmixture was diluted with ethyl acetate and washed with saturatedammonium chloride aqueous and brine. After concentration, the crudeproduct was dried on vacuum pump. The crude pyrazinone amide (50 mg,0.11 mmol) was dissolved in dry DMF (1 ml) and was treated with1-iodoethanol (29 mg, 0.18 mmol) and potassium carbonate (24 mg, 0.18mmol). The reaction mixture was stirred at room temperature for 1 hour.The mixture was diluted with ethyl acetate and washed with water andbrine. After concentration, the final product was purified via columnchromatography on silica gel, as a yellow solid.

¹H NMR (CDCl₃) (δ, ppm): 8.35 (m, 2H), 7.53 (m, 3H), 7.46 (bs, 1H,),7.37 (t, J=17 Hz, 1H), 4.27 (d, J=6 Hz, 2H), 4.08 (d, J=6 Hz, 2H).

MS (ESI): m/e 456 (M+1)⁺

TABLE 6

Example (m/e) # R⁷ R⁶ R³ R¹ (M + H) 121 4-F —CF₃ —CH₃ —CONH₂ 410 122 5-F—CF₃ H —CONH₂ 396 123 H —CF₃ —CH₂CH₂OH —CONH₂ 422 124 H —CF₃ —CH₂CH₂F—CONH₂ 424 125 H —OCF₃ —CH₂CH₂OH —CONH₂ 438 126 H —OCF₃ —CH₂CH₂CH₂OH—CONH₂ 452 127 H —OCF₃ —CH₂CONH₂ —CONH₂ 451 128 H —OCF₃ —CH(CH₃)CONH₂—CONH₂ 465 129 H —OCF₃ —CH₂CH₃ —CONH₂ 422 130 H —OCF₃ —CH₂CH₂F —CONH₂440 131 H —CF₃ —CH₂CONH₂ —CONH₂ 435 132 H —OCF₃ —CH₂SO₂NH₂ —CONH₂ 487133 3-F —CF₃ —CH₂SO₂NH₂ —CONH₂ 471 134 H —CF₃ —CH₂CH₃ —CONH₂ 406 135 H—CF₃ —CH₂CH₂CH₂OH —CONH₂ 436 136 H —OCF₃ —CH₂CH₂Cl —CONH₂ 456 137 H—OCF₃ —CH₂CH₂N₃ —CONH₂ 463 138 H —OCF₃ —CH₂CH₂NH₂ —CONH₂ 437 139 H —CF₃—CH(CH₃)CONH₂ —CONH₂ 449 140 H —OCF₃ —CH₂CONHCH₃ —CONH₂ 464 141 4-F —CF₃—CH₂CONH₂ —CONH₂ 453 142 4-F —CF₃ —CH₂CH₂OH —CONH₂ 440 143 4-F —CF₃—CH₂CH₃ —CONH₂ 424 144 4-F —CF₃ H —CONH₂ 394 145 5-F —CF₃ —CH₂CH₂OH—CONH₂ 440 146 5-F —CF₃ —CH₂CONH₂ —CONH₂ 453 147 H —OCF₃ —CH₂C(═O)CH₃—CONH₂ 450

TABLE 7

Example # R⁴ R³ MS Data (m/e, M + 1) 148 F H 430 149 F CH₂CONH₂ 487 150F CH₂CH₂OH 474 151 F CH₃ 444 152 H H 412 153 H CH₂CONH₂ 468 155 H CH₃426

TABLE 8

Example # R³ MS Data (m/e, M + 1) 156 CH₂CONH₂ 467 157 CH₂CH₂OH 454

TABLE 9

Example # R⁶ R³ MS Data (m/e, M + 1) 158 OCF3 CH₂CONH₂ 467 159 OCF3CH(CH₃)CONH₂ 481 160 OCF3 CH₂CH₂OH 454 161 OCF3 CH₂CH₂CH₂OH 468 162 OCF3CH₂CH₃ 438 163 CF3 CH₂CONH₂ 451 164 CF3 CH(CH₃)CONH₂ 465 165 CF3CH₂CH₂OH 438 166 CF3 CH₂CH₂CH₂OH 452 167 CF3 CH₂CH₃ 422

TABLE 10

Example # R³ MS Data (m/e, M + 1) 168 H 394 169 CH₂CONH₂ 451 170CH₂CH₂OH 438 171 CH(CH₃)CONH₂ 465 172 CH₂CH₂CH₂OH 452 173 CH₂CH₃ 422 174CH₂CONHCH₃ 465 175 CH₂CON(CH₃)₂ 479 176 CH₂CO₂CH₃ 466

EXAMPLE 177

Step 1: Preparation of

To a solution of 2-bromo-4-fluorophenol (5 g) in THF (100 mL) at 0° C.were added N-methylmorpholine (5.25 g) and Phenyl chlorodithioformate(5.18 g). The reaction mixture was stirred at 0° C. for 2 h and thendiluted with EtOAc (100 mL), washed with water (100 mL) (2×) and thenbrine (100 mL). The organic layer was dried over Na₂SO₄ and concentratedin vacuo to give the desired xanthate as a yellow solid.

¹H NMR (CDCl₃): 7.65 (m, 2H), 7.51 (m, 2H), 7.38 (m, 1H), 7.08-7.16 (m,3H).

MS (ESI): m/e 344 (M+1)⁺

Step 2: Preparation of

A solution of the xanthate (1 g) (from Step 1 above) in CH₂Cl₂ (10 mL)was added to HF/pyridine (4.4M, 4 mL) placed in a 250 ml plastic bottle.The bottle was cooled to −78° C. and 1,3-dibromo-5,5-dimethyl hydantoin(5.1 g) was added in portion while stirring. The reaction mixture wasallowed to warm up to room temperature; the progress of the reaction wasmonitored by NMR. The reaction mixture was carefully neutralized bypouring into a mixture of 15 g NaOH/100 g ice. The resulting mixture wasfiltered through a pad of celite and washed with ether. The filtrate wasseparated, the organic layer was washed with 10% KOH and 1N HCl, driedover Na₂SO₄, purified by column chromatography on silica gel (usinghexane) to give the desired aryl bromide as a colorless oil.

¹H NMR (CDCl₃): 7.42 (m, 1H), 7.33 (m, 1H), 7.38 (m, 1H), 7.09 (m, 1H).

MS (ESI): m/e 192 (M+1)⁺

Step 3: Preparation of

To a solution of the aryl bromide (from Step 2 above) (5 g) in THF (25mL) was added Isopropylmagnesium chloride (15 mL, 2.0M in THF) at roomtemperature. After stirring at the ambient for 2 h, B(OiPr)₃ was addedto the reaction and stirred overnight. The reaction was quenched with 1NHCl, stirred at room temperature for 30 min and extracted with EtOAc.The residue obtained after removal of the solvent in vacuo, wasdissolved in 10% KOH, extracted with ether. The aqueous phase wasacidified with concentrated HCl and extracted with EtOAc. The organiclayer was dried over Na₂SO₄ and concentrated to give the aryl boronicacid as a white solid.

¹H NMR (CDCl₃): 7.28-7.32 (m, 1H), 7.17-7.22 (m, 2H)

MS (ESI): m/e 225 (M+1)⁺

Step 4: Preparation of:

To a 250 ml Schlenk flask equipped with a stirring bar was charged with1.0 g of boronic acid (from Step 3 above) and 1.0 g of 3-bromo-phenylpyrazinone carboxylic acid (from Step 2 of Example 1), followed by 15 mlEtOH and 20 ml 1M Na₂CO₃. After reaction mixture was flushed with N₂,Pd(dppf)Cl2 (69 mg) was then added. Reaction mixture was heated at 95°C. for 1 hour and then at 80° C. overnight. After reaction mixture wascooled to room temperature, volatiles were removed under vacuum. To theresidue was added 80 ml 2% KOH. Resulting mixture was filtered through apad of celite to remove highly colored palladium residue. Filtrate wasacidified with 3N HCl and extracted with 75 ml EtOAc (2 times). Organicswere dried over Na2SO4, filtered and concentrated to give 1.2 g crudeproduct. This material was further purified by recrystallization frommixed solvent of CH₃CN and H₂O to give 0.71 g pale brown solid as thefirst crop material.

MS (ESI): m/e 395 (M+1)⁺

EXAMPLE 178 Preparation of:

To a solution of the carboxylic acid (from Step 4, Example 177) (0.707g) in anhydrous DMF (5 mL) was added 1,1′-carbonyldiimidazole (0.5 g).The resulting reaction mixture was stirred at room temperature for 10minutes and at 50° C. for 15 more minutes. After cooling to roomtemperature, NH₄OAc (1.0 g) was added as a solid. After stirring at roomtemperature over night, reaction mixture was diluted with water (100mL). The precipitate formed was filtered, washed with water (100 mL) andair dried. The final product product was isolated as pale yellow solid(0.67 g).

MS (ESI): m/e 394 (M+1)⁺

EXAMPLE 179 AND 180

To a mixture of the pyrazinone (Example 32) (0.1 g), K₂CO₃ (36 mg) inDMF (1 mL) was treated with a solution of2-p-toluenesulfonato-1,3-propane diol (prepared according to theprocedure described by Kurimura, M.; Achiwa, K.; Chem Pharm Bull, Jap.1993, 41, 627-629) (196 mg) in DMF (3 mL) was added to the reactionmixture via a syringe pump over 2 h while the reaction mixture washeated at 90° C. After heating at 90° C. for an additional 2 h, thereaction was cooled to room temperature and water (1.5 mL) H₂O and 5drops of TFA were added. The resulting solution was injected into areversed-phase HPLC column and purified by Gilson HPLC (10-90%CH₃CN/H₂0) to give 52 mg sticky material. This material was furtherpurified on prep-TLC plate by eluting with 3:2 acetone/ethylacetate togive 179 (22 mg) and 180 (10.5 mg) as white solids.

Example 179: MS (ESI): m/e 376 (M+1)⁺

¹H NMR (CD₃OD): 8.45 (m, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 7.62 (m, 2H),7.55 (t, J=7.8 Hz, 1H), 7.48 (t, J=8.6 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H),5.04 (m, 1H), 4.0 (m, 2H), 3.9 (m, 2H)

Example 180: MS (ESI): m/e 376 (M+1)⁺

¹H NMR (CD₃OD): 8.47 (d, J=8.0 Hz, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 7.6(m, 2H), 7.55 (t, J=7.8 Hz, 1H), 7.48 (t, J=8.6 Hz, 1H), 7.39 (d, J=7.6Hz, 1H), 4.48 (dd, J=13.2, 2.9 Hz, 1H), 4.03 (m, 1H), 3.84 (m, 1H), 3.60(d, J=5.3 Hz, 2H).

TABLE 11

Example (m/e) # R⁷ R⁶ R⁵ R⁴ R³ (M + H) 181 H OCF₃ H H C(CH₃)₂CONH₂ 461182 5-Cl Cl H H CH₂CONH₂ 418 183 4-CF₃ CF₃ H H CH₂COOH 486 184 4-CF₃ CF₃H H CH₂CONH₂ 485 185 H Cl H H CH₂CONH₂ 383 186 3-Cl Cl H H CH₂CONH₂ 418187 5-CF₃ CF₃ H H CH₂CONH₂ 485 188 H OCF₃ H H CH(CH₃)COOH 448 189 H OCF₃H H CH(CH₃)CONH₂ 447 190 H CF₃ H H CH(CH₃)CONH₂ 431 191 H OCF₃ H H

460 192 H OCF₃ H H CH(CH₃)COCH₃ 446 193 H OCF₃ H F CH₂CONH₂ 451 194 6-FCF₃ H H CH₂CONH₂ 435 195 H OCF₃ F H CH₂CONH₂ 451 196 6-F CF₃ H HCH(CH₃)CONH₂ 449 197 H OCF₃ F H CH(CH₃)CONH₂ 465 198 4-F OCF₃ F HCH₂CONH₂ 469 199 4-F OCF₃ F H CH(CH₃)CONH₂ 483 200 H CF₃ H F CH₂CONH₂435 201 3-F CF₃ H H CH₂CONH₂ 435 202 4-Cl CF₃ H H CH₂CONH₂ 451 203 HOCF₃ H F CH(CH₃)CONH₂ 465 204 6-F CF₃ H H CH₂CONHCH₃ 449 205 6-F CF₃ H HCH₂CON(CH₃)₂ 463 206 H CF₃ H H CH(CONH₂)₂ 460 207 H OCF₃ H H CH(CONH₂)₂476 208 6-F CF₃ H H CH(CONH₂)₂ 478 209 H CF₃ H H CH₂CONHCH₃ 431 210 HCF₃ H H CH₂CON(CH₃)₂ 445 211 4-CF₃ CF₃ H F CH₂CONH₂ 503 212 H OCF₃ H HCH₂CON(CH₃)₂ 461 213 H OCF₃ H H CH₂CONHCH₃ 447 214 H OCF₃ F H CH₂CONHCH₃465 215 H OCF₃ H F CH₂CONHCH₃ 465 216 6-F CF₃ H H CH₂CONH(CH₂)₂OH 479217 H CF₃ H F CH₂CONHCH₃ 449 218 H OCH₂CF₃ H H CH₂CONH₂ 447 219 HOCH₂CF₂CF₃ H H CH₂CONH₂ 497 220 6-F CF₃ H H

475 221 H CF₃ H H

457 222 6-F CF₃ H H CH₂CONHCH(CH₃)₂ 477 223 6-F CF₃ H H CH₂CONHC(CH₃)₃491 224 H CF₃ H H CH₂CONHC(CH₃)₃ 459 225 4-F OCF₃ H H CH₂CONH₂ 451 226 HCF₃ H H CH₂CONHCH₂CH₃ 445 227 H CF₃ H F CH₂CONHCH₂CH₃ 463 228 6-F CF₃ HH

493 229 6-F OCF₃ H H CH₂CONH₂ 451 230 6-F CF₃ H H

511 231 5-F OCF₃ H H CH₂CONH₂ 451 232 6-F OCF₃ H H CH₂COOH 452 233 HOCF₃ H OCH₂Ph CH₂CONH₂ 539 234 H OCF₃ H OCH₂Ph CH(CH₃)CONH₂ 553 235 HCF₃ H H

485 236 5-I OCF₃ H H CH₂CONH₂ 559 237 6-F CF₃ H H CH₂COCH₃ 434 238 H CF₃H H CH₂COCH₃ 416 239 H CF₃ H H

514 240 H CF₃ I I CH₂CONH₂ 669 241 5-F OCF₃ H F CH₂CONH₂ 469 242 4-F CF₃H F CH₂CONH₂ 453 243 H OCF₃ H H CH₂COCH₃ 432 244 H CF₃ H H

475 245 H OCF₃ Br H CH₂CONH₂ 512 246 H OCF₃ H F CH₂COCH₃ 450 247 5-F CF₃H H CH₂COCH₃ 434 248 5-F CF₃ H H

475 249 H OCF₃ F H CH₂COCH₃ 450

EXAMPLE 250

Step 1: Preparation of:

A 50-ml round-bottom flask fitted with a stirbar and septum was flushedwith N₂ and charged with the keto methyl ester (from Step 1 Example 1)(0.500 g), anhydrous methanol (10 mL), and methyl 2,3diaminopropionate(0.772 g) [prepared from 2,3-diaminopropionic acid, commerciallyavailable from Sigma-Aldrich]. To the resulting mixture (a whitesuspension) was added sodium methoxide solution (3.4 mL, 25% w/w)dropwise over 5 min. The yellow reaction mixture, thus obtained, wasstirred at room temperature under air for 30 min before beingconcentrated in vacuo. The resulting yellow solid was acidified with 1NHCl (50 mL) and extracted (2×) with EtOAc (50 mL). The combined organicphase was dried over sodium sulfate and concentrated under reducedpressure. The crude pyrazinone carboxylic acid obtained was dried undervacuum and then purified by reversed-phase chromatography usingacetonitile and water.

¹H NMR (d₆-DMSO): 8.49 (t, J=1.8 H_(z), 1H), 8.42 (d, J=8.1 H_(z), 1H),8.09 (s, 1H), 7.66 (m, 1H), 7.43 (t, J=8.0 H_(z), 1H).

Step 2: Preparation of

To a 250 ml Schlenk flask equipped with a stirring bar was charged withof 2-trifluoromethoxyphenyl boronic acid (1.0 g) and thebromophenylpyrazinone carboxylic acid (from Step 1 above ) (1.0 g),followed by EtOH (15 mL) and 1M Na₂CO₃ (20 mL). The reaction mixture wasflushed with N₂ and Pd(dppf)Cl2 (69 mg) was added. The mixture washeated at 95° C. for 1 h and then at 80° C. overnight. The reaction wascooled to room temperature and volatiles were removed under reducedpressure. The residue obtained was dissolved in 2% KOH (80 mL) and theresulting mixture was filtered through a pad of celite to remove highlycolored palladium residue. The filtrate was acidified with 3N HCl andextracted with EtOAc (75 mL; 2×). The organic phase was dried overNa₂SO₄, filtered and concentrated in vacuo to give the crude product(1.2 g). This material was further purified by recrystallization frommixed solvent of CH₃CN and H₂O to give 0.71 g pale brown solid.

¹H NMR (CD₃OD): 8.41 (s, 1H), 8.36 (d, J=7.8 H_(z), 1H), 8.24 (s, 1H),7.66 (d, J=7.3 Hz, 1H), 7.60 (t, J=7.6 H_(z), 1H), 7.52 (d, J=6.8 Hz,1H), 7.42 (m, 3H).

MS (ESI): m/e 377 (M+1)⁺

Step 4: Preparation of:

To a solution of the carboxylic acid from Step 2 (0.707 g) in anhydrousDMF (5 mL) was added CDI. The resulting reaction mixture was stirred atroom temperature for 10 minutes and at 50° C. for 15 more minutes. Aftercooling to room temperature, NH₄OAc (1.0 g) was added as a solid. Afterstirring at room temperature over night, reaction mixture was dilutedwith water (100 mL). The precipitate formed was filtered and washed withwater and air dried to yield the final amide product as pale yellowsolid (0.67 g).

¹H NMR (CD₃OD): 8.51 (s, 1H), 8.42 (m, 1H), 8.08 (s, 1H), 7.6 (m, 3H),7.48 (m, 2H), 7.43 (m, 1H).

MS (ESI): m/e 376 (M+1)⁺

TABLE 12

Example # R⁷ R⁶ R⁵ R⁴ (m/e) (M + H) 251 4-F CF₃ H H 422 252 6-F CF₃ H H422 253 3-F CF₃ H H 422 254 H CF₃ F H 422 255 H CF₃ H F 422 256 5-CF₃OCF₃ H H 488 257 4-F OCF₃ H H 438 258 H OCF₃ F H 438 259 H OCF₃ H F 438260 4-F CF₃ H F 440 261 3-F CF₃ H F 440 262 H O CH₂CF₂CF₃ F H 502 2634-F OCF₃ F H 456 264 4-CF₃ CF₃ H H 472 265 5-Cl Cl H H 405 266 5-CF₃ CF₃H H 472 267 5-F CF₃ H H 422 268 4-F OCF₃ H H 438 269 5-F OCF₃ H H 438270 H OCF₃ H OCH₂Ph 526 271 H OCF₃ Br H 499 272 4-Cl CF₃ H H 451

TABLE 13

Example (m/e) # R⁷ R⁶ R⁵ R⁴ R³ (M + H) 273 H OCF₃ H H CH₃ 433 274 H CF₃H H CH₃ 417 275 H CF₃ H H H 403 276 H OCF₃ H H H 419 277 4-F CF₃ H H H421 278 4-F CF₃ H H CH₃ 435 279 4-F CF₃ H H CH₂CH₂OH 465 280 3-F CF₃ H HH 421 281 3-F CF₃ H H CH₃ 435 282 3-F CF₃ H H CH₂CH₂OH 465 283 4-Cl CF₃H H CH₃ 451 284 5-CF₃ CF₃ H H CH₃ 485 285 4-Cl CF₃ H H H 437 286 5-CF₃CF₃ H H H 471 287 4-F OCF₃ H H H 437 288 4-F OCF₃ H H CH₃ 451 289 4-FOCF₃ H H CH₂CH₂OH 481 290 4-Cl CF₃ H H CH₂CH₂OH 481 291 5-CF₃ CF₃ H HCH₂CH₂OH 515 292 H OCH₂CF₂CF₃ H H H 483 293 H OCH₂CF₂CF₃ H H CH₃ 497 294H OCH₂CF₂CF₃ H H CH₂CH₂OH 527 295 H OCH₂CF₃ H H H 433 296 H OCF₃ F H H437 297 H CF₃ F H H 421 298 H OCH₂CF₃ H H CH₃ 447 299 H OCF₃ F H CH₃ 451300 H CF₃ F H CH₃ 435 301 H OCF₃ F H CH₂CH₂OH 481 302 H CF₃ F HCH₂CH═CH₂ 461 303 H OCF₃ F H CH₂CH═CH₂ 477 304 H CF₃ F H CH₂CH═CH₂ 465305 H CF₃ F H CH₂CH₂OCH₃ 479

TABLE 14

Example (m/e) # R⁷ R⁶ R⁵ R⁴ R³ (M + H) 306 H OCF₃ H H CH₂CH₂OCH₃ 434 3076-F CF₃ H H CH₂CH₂OCH₃ 436 308 6-F CF₃ H H CH₂CH₂OCH₂CH₃ 450 309 H OCF₃H H CH₂CH₂CH₃ 418 310 H OCF₃ H H CH(CH₂OH)CH₂OH 450 311 H CF₃ H HCH(CH₂OH)CH₂OH 434 312 H OCF₃ H H

538 313 6-F OCF₃ H H CH(CH₂OH)CH₂OH 468 314 H CF₃ H F CH(CH₂OH)CH₂OH 452315 H CF₃ H F CH₂CH(OH)CH₂OH 452 316 H OCF₃ H H CH₂CH₂CH₂CH₃ 432 317 HCF₃ H H CH₂CH(OH)CH₃ 418 318 6-F CF₃ H H CH₂CH(OH)CH₃ 436 319 6-F OCF₃ HH CH₂CH(OH)CH₂OH 468 320 H OCF₃ H H

414 321 H OCF₃ H H CH₂CH₂CH₂CH₂CH₃ 446 322 6-F CF₃ H H

416 323 H OCF₃ H H CH₂C(CH₃)₂CH₂OH 462 324 H OCF₃ H H CH₂CH₂CONH₂ 416325 H OCF₃ H H CH₂CH₂SCH₃ 450 326 6-F CF₃ H H CH₂CH₂SCH₃ 452 327 H OCF₃H H

489 328 H OCF₃ H H CH₂CH₂SO₂CH₃ 482 329 6-F CF₃ H H CH₂CH₂SO₂CH₃ 484 3306-F CF₃ H H

491 331 6-F CF₃ H H CH₂CH₂CH₂OH 436 332 6-F CF₃ H H CH₂SCH₃ 438 333 6-FCF₃ H H CH₂CH₂CH₂SCH₃ 498 334 6-F CF₃ H H CH₂CH₂CH₂SO₂CH₃ 530 335 H OCF₃H H CH₂CH₂NHCONH₂ 462 336 6-F CF₃ H H

432 337 H OCF₃ H H CH₂CF₃ 458 338 H OCF₃ H H CH₂CF₂CF₃ 508 339 H CF₃ H HCH₂CH₂CH₂OH 418 340 H CF₃ H H

414 341 H OCF₃ H H

430 342 H CF₃ H H CH₂SCH₃ 420 343 H OCF₃ H H CH₂SCH₃ 436 344 H OCF₃ H HCH₂SO₂CH₃ 468 345 6-F CF₃ H H CH₂SO₂CH₃ 470 346 6-F CF₃ H H CH₂CH₃ 406347 6-F CF₃ H H CH₂CH₂CH₃ 420 348 H OCF₃ H H CH₂SO₂NHC(CH₃)₃ 525 349 HOCF₃ H H CH₂SO₂NH₂ 469 350 H OCF₃ H H

485 351 4-F CF₃ H H CH₂SO₂NH₂ 471 352 H CF₃ H H CH₂SO₂NH₂ 452 353 4-FOCF₃ H H CH₂SO₂NH₂ 452 354 6-F CF₃ H H CH₂SO₂NH₂ 436 355 H CF₃ H HCH₂SO₂CH₃ 452 356 H OCF₃ F H CH₂SO₂CH₃ 486 357 4-F CF₃ H H CH₂CH₃ 422358 4-F OCF₃ H H CH₂CH₂CH₂OH 470 359 4-Cl CF₃ H H CH₂SO₂NH₂ 487 360 3-FCF₃ H H CH₂SO₂NH₂ 471 361 4-F CF₃ H H CH₂SO₂NHCH₃ 485 362 H CF₃ H FCH₂CH₂CH₂OH 454 363 H OCF₃ F H CH₂CH₂F 436 364 H OCF₃ H F CH₂CH₂F 436365 4-F OCF₃ F H CH₂CH₂F 455 365 6-F CF₃ H H CH₂CH₂F 424 366 H CF₃ H FCH₂CH₂F 424 367 4-CF₃ CF₃ H H CH₂SO₂NH₂ 521 367 H OCF₃ H F CH₂SO₂NH₂ 487368 H CF₃ H F CH₂SO₂NH₂ 471 369 H OCF₃ H F CH₂SO₂NHCH₃ 501 370 H CF₃ H FCH₂SO₂NHCH₃ 485 371 H CF₃ H H CH₂CH₂F 405 372 H OCF₃ H H CH₂CH₂F 421 3733-F CF₃ H H CH₂CH₂F 424 374 4-Cl CF₃ H H CH₂CH₂F 440 375 5-CF₃ CF₃ H HCH₂CH₂F 474 376 H OCF₃ F H

507 377 H OCF₃ H F CH₂CH₂F 437 378 H OCF₃ F H CH₂CH₂F 437 379 5-F CF₃ HH CH₂CH₃ 406 380 5-F CF₃ H H CH₂CH₂F 424 381 H CF₃ H H CH(CONH₂)₂ 460382 H OCF₃ H H CH(CONH₂)₂ 476 383 6-F CF₃ H H CH(CONH₂)₂ 479 384 6-F CF₃H H CH₂CONHCH₂CH₂OH 480

1. A compound represented by Formula (I):

or pharmaceutically acceptable salts thereof, wherein R¹ and R² eachindependently is (a) H, (b) C₁-C₆-alkyl, optionally substituted with oneor more substituents selected from the group consisting of: F, CF₃, OH,NR^(a)R^(b), COOH, CONR^(a)R^(b), SO₂NR^(a)R^(b), C(═NH)NH₂, tetrazolyl,triazolyl, oxazolyl, oxadiazolyl, isooxazolyl, thiazolyl, pyrazolyl,pyridyl, pyrimidinyl, pyrazinyl, phenyl, piperidinyl, morpholinyl,pyrrolidinyl and piperazinyl, (c) —C(═O)R^(a), COOR^(a), CONR^(a)R^(b),(d) —C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl, (e) NR^(a)R^(b),—N(COR^(a))R^(b), —N(SO₂R^(a))R^(b), or (f) tetrazolyl, triazolyl,oxazolyl, oxadiazolyl, isooxazolyl, thiazolyl, pyrazolyl, pyridyl,pyrimidinyl, pyrazinyl, phenyl, piperidinyl, morpholinyl, pyrrolidinylor piperazinyl, any of which is optionally substituted with 1-3substituents independently selected from the group consisting of: F, Cl,Br, I and CN; R^(a) is (a) H, (b) C₁-C₆-alkyl, optionally substitutedwith one or more substituents independently selected from the groupconsisting of CF₃ and O—(C₁-C₄)alkyl, (c)C₀-C₄-alkyl-(C₁-C₄)-perfluoroalkyl, (d) NH₂, (e) C₁-C₄-alkyl-phenyl,C₁-C₄-alkyl-pyridyl, or (f) C₃-C₇-cycloalkyl, optionally substitutedwith one or more substituents selected from the group consisting of F,Cl, Br, OH, —O—C₁-C₄-alkyl, and C₁-C₄-alkyl; R^(b) is (a) H, or (b)C₁-C₆-alkyl; R is: (a) H, (b) —C₁-C₄-alkyl, optionally substituted withone or more substituents independently selected from the groupconsisting of: F, CF₃, Cl, N, OH, O—(C₁-C₄)alkyl, S(O)₀₋₂—(C₁-C₄)alkyl,O—CONR^(a)R^(b), NR^(a)R^(b), N(R^(a))CONR^(a)R^(b), COOR^(a), CN,CONR^(a)R^(b), SO₂NR^(a)R^(b), N(R^(a))SO₂NR^(a)R^(b), —C(═NH)NH₂,tetrazolyl, triazolyl, imidazolyl, oxazolyl, oxadiazolyl, isooxazolyl,thiazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidinyl,pyrazinyl, phenyl, piperidinyl, morpholinyl, pyrrolidinyl andpiperazinyl, or R^(a) and R^(b), together with N to which they areattached, may form a C₃-C₇-cycloalkyl or a C₃-C₇-heterocycloalkyl,wherein said cycloalkyl and heterocycloalkyl is optionally substitutedwith one or more substituents selected from the group consisting of: F,Cl, Br, OH, —O—C₁-C₄-alkyl, and C₁-C₄-alkyl, (c)—C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl, or (d) C₁-C₄-alkyl-C(═O)—R^(a),—C₁-C₄-alkyl-C(═O)—C₁-C₄-perfluoroalkyl, or (e)—C₁-C₄-alkyl-C₃-C₇-cycloalkyl, wherein said cycloalkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: F, Cl, Br, OH, —O—C₁-C₄-alkyl, and C₁-C₄-alkyl; R⁴ and R⁵each independently is: (a) H, (b) —C₁-C₆-alkyl, optionally substitutedwith one or more substituents independently selected from the groupconsisting of: F, CF₃ and —O—(C₁-C₄)alkyl, (c) —O—C₀-C₆-alkyl,—O-phenyl, —O—C₁-C₄-alkyl-phenyl, —O-pyridyl, —O—C₁-C₄-alkyl-pyridyl,wherein phenyl and pyridyl are optionally substituted with 1-3substituents independently selected from the group consisting of: F, Cl,Br, I and CN, (d) —C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl,—O—C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl, or (e) F, Cl, Br, I; and R⁶, R⁷ andR⁸ each independently is: (a) H, (b) C₁-C₆-alkyl, (c) —O—C₁-C₆-alkyl,optionally substituted with one or more substituents independentlyselected from the group consisting of: F and CF₃, (d)—C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl, —O—C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl,(e) —O-phenyl, —O—C₁-C₄-alkyl-phenyl, —O-pyridyl,—O—C₁-C₄-alkyl-pyridyl, wherein phenyl and pyridyl are optionallysubstituted with 1-3 substituents independently selected from the groupconsisting of: F, Cl, Br, I, and CN, or (f) F, Cl, Br, I, —OR^(a),phenyl or pyridyl, wherein phenyl and pyridyl are optionally substitutedwith one or more substituents independently selected from the groupconsisting of: F, Cl, Br, I and CN, with the proviso that when R⁶ and R⁷are present on adjacent carbon atoms, R⁶ and R⁷, together with thebenzene ring to which they are attached, may form a bicyclic aromaticring selected from the group consisting of: naphthyl, quinolinyl andbenzothiazolyl, any aromatic ring of which is optionally substitutedwith 1-4 substituents independently selected from F, Cl, Br, I and CN.2. The compound of claim 1 described by the chemical Formula (I), or apharmaceutically acceptable salt thereof, wherein R₆ is other than H andis attached at the ortho position, and all other variables are aspreviously defined.
 3. The compound of claim 2, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is H, COOR^(a) or CONR^(a)R^(b), andall other variables are as previously defined.
 4. The compound of claim1 represented by Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein R⁶ is OR^(a) orC₀-C₄-alkyl-C₁-C₄-perfluoroalkyl, and all other variables are aspreviously defined.
 5. The compound of claim 1 represented by FormulaIb:

or a pharmaceutically acceptable salt thereof, wherein R⁶ is OR^(a) orC₀-C₄-alkyl-C₁-C₄-perfluoroalkyl; R⁷ is H, F, Cl, Br or I; and all othervariables are as previously defined.
 6. The compound of claim 1represented by Formula Ic:

or a pharmaceutically acceptable salt thereof, wherein R⁴ and R⁵ eachindependently is H, F, Cl, Br or I; R⁶ is OR^(a) orC₀-C₄-alkyl-C₁-C₄-perfluoroalkyl; R⁷ is H, F, Cl, Br or I; and all othervariables are as previously defined.
 7. The compound of claim 1represented by Formula Id:

or a pharmaceutically acceptable salt thereof, wherein R⁴ is F, Cl, Bror I; R⁶ is OR^(a) or C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl; R⁷ is H, F, Cl,Br or I; and all other variables are as previously defined.
 8. Acompound selected from

and pharmaceutically acceptable salts thereof.
 9. A compound accordingto claim 1 represented by

R⁶ R³ R² R¹ —OCF₃ H H —CONH₂ —OCF₃ CH₃ H —COOH —OCF₃ CH₃ —CONH₂ H —CF₃CH₃ —CONH₂ H —CF₃ H H —COO-t-Bu —CF₃ H H —CONH-t-Bu —CF₃ H H —COOH—OCH₂CF₂CF₃ H H —CONH₂ —OCH₂CF₂CF₃ H H —COOH —OCH₂CF₃ H H —CONH₂—OCH₂CF₃ CH₃ H —CONH₂ —OCH₂CF₃ H —CONH₂ H —OCH₂CF₃ CH₃ —CONH₂ H—OCH₂CF₂CF₃ CH₃ H —CONH₂ —OCH₂CF₃ H H —COOH —CF₃ —CH₂CF₃ H —CONH₂ —CF₃—C(CH₃)₃ H —CONH₂ —CF₃ —CH(CH₃)₂ H —CONH₂ —CF₃ —CH₂CH₃ H —CONH₂ —OCF₃CH₃ —CONH₂ —CONH₂

or a pharmaceutically acceptable salt thereof.
 10. A compound accordingto claim 1 represented by

R⁷ R⁶ R³ R² R¹ 4-CF₃ —CF₃ —CH₃ H —CONH₂ 4-CF₃ —CF₃ —CH₃ —CONH₂ H 5-F—OCF₃ —CH₃ H —CONH₂ 5-CF₃ —OCF₃ —CH₃ H —CONH₂ 5-F —OCF₃ H H —CONH₂ 5-F—OCH₂CF₂CF₃ H H —CONH₂ 5-F —OCH₂CF₃ H H —CONH₂ 5-F —OCH₂CF₂CF₃ —CH₃ H—CONH₂ 5-F —OCH₂CF₃ —CH₃ H —CONH₂ 6-F —CF₃ H H —CONH₂ 3-F —CF₃ H H—CONH₂ 6-F —CF₃ —CH₃ H —CONH₂ 3-F —CF₃ —CH₃ H —CONH₂ 5-F —CF₃ —CH₃ H—CONH₂ 4-F —CF₃ —CH₃ H —CONH₂ 4-F —CF₃ H H —CONH₂ 5-F —CF₃ H H —CONH₂5-CH₃ —CF₃ —CH₃ H —CONH₂ 4-CH₃ —CF₃ —CH₃ H —CONH₂

or a pharmaceutically acceptable salt thereof.
 11. A compound accordingto claim 1 represented by

R⁷ R⁶ R⁵ R⁴ R³ R² R¹ H —OCF₃ F H —CH₃ —CONH₂ H H —OCF₃ F H —CH₃ H —CONH₂H —OCF₃ H F —CH₃ H H H —OCF₃ H F —CH₃ H —CONH₂ H —OCH₂CF₃ H F —CH₃ H—CONH₂ H —OCF₃ H F —CH₃ H —COOH 5-F —OCF₃ F H —CH₃ H —CONH₂ 5-F —OCF₃ HF —CH₃ H —CONH₂ H —CF₃ H F —CH₃ H —CONH₂ H —CF₃ F H —CH₃ H —CONH₂ H—OCF₃ H F H H —CONH₂ H —OCF₃ F H H H —CONH₂ 5-F —OCF₃ F H H H —CONH₂ H—CF₃ F H —CH₃ H —COOH 5-F —OCH₂CF₂CF₃ F H —CH₃ H —CONH₂ H —CF₃ H F —CH₃H —COOH H —OCF₃ F H —CH₃ H —COOCH₃ H —CF₃ F H —CH₃ H —COOCH₃ H —CF₃ F H—CH₃ H —COOCH₃ 5-F —OCH₂CH₃ F H —CH₃ H —COOCH₃ 5-F —OCH₂CF₃ F H —CH₃ H—COOCH₃ H —OCF₃ F H H H —COOH H —OCF₃ H F H H —COOH 5-F —OCH₂CF₂CF₃ F H—CH₃ H —COOH H —CF₃ H F H H —CONH₂ H —CF₃ Br H —CH₃ H —COOCH₃ H —CF₃ F HH H —CONH₂ H —CF₃ Br H —CH₃ H —CONH₂ 5-F —CF₃ H F —CH₃ H —CONH₂ H —CF₃Br H H H —COOCH₃ H —CF₃ Br H H H —COOH 5-F —OCH₂CF₃ F H H H —CONH₂ 3-F—CF₃ F H —CH₃ H —CONH₂ 3-F —CF₃ H F —CH₃ H —CONH₂ 5-F —CF₃ F H —CH₃ H—CONH₂ 4-F —CF₃ F H —CH₃ H —CONH₂ 4-F —CF₃ H F H H —CONH₂

or a pharmaceutically acceptable salt thereof.
 12. A compound accordingto claim 1 represented by

R⁷ R⁶ R⁴ R³ R² R¹ H —OCF₃ F —CH₃ H —CONH₂ H —OCF₃ F —CH₃ —CONH₂ H H—OCF₃ F —CH₃ H —COOH H —OCF₃ F H H —CONH₂ H —OCF₃ F H H —COOH H —CF₃ F—CH₃ H —CONH₂ H —CF₃ F —CH₃ H —COOH 5-F —OCH₂CF₂CF₃ F —CH₃ H —CONH₂ 5-F—OCH₂CF₃ F —CH₃ H —CONH₂ H —OCF₃ F —CH₃ H —COOCH3 5-F —CF₃ F —CH₃ H—CONH₂ H —CF₃ F H H —CONH₂ 3-F —CF₃ F —CH₃ H —CONH₂

or a pharmaceutically acceptable salt thereof.
 13. A compound accordingto claim 1 represented by

R⁷ R⁶ R⁵ R⁴ R³ R² R¹ H OCF₃ H H CH₂CONH₂ H CONH₂ H CF₃ H H CH₂CONH₂ HCONH₂ H OCF₃ H H CH₂COOH H CONH₂ H OCF₃ H H CH₂COO-tBu H CONH₂ H OCF₃ HH CH₂CN H CONH₂ H CF₃ H H CH₂CN H CONH₂ H CF₃ H H CH₂COOH H CONH₂ H CF₃H H CH₂COO-tBu H CONH₂ H OCF₃ H H

H CONH₂ H CF₃ H H

H CONH₂ H CF₃ H H

H CONH₂ H OCF₃ H H

H CONH₂ H OCF₃ H H CH₂CH₂OH H CONH₂ H CF₃ H H CH₂CH₂OH H CONH₂ H OCF₃ HH CH₂CH₂NH₂ H CONH₂ H CF₃ H H CH₂CH₂NH₂ H CONH₂ H OCF₃ H H CH₂CH₂N(CH₃)₂H CONH₂ H CF₃ H H CH₂CH₂N(CH₃)₂ H CONH₂ 4-F CF₃ H H CH₂CONH₂ H CONH₂ 5-FCF₃ H H CH₂CONH₂ H CONH₂ H CF₃ F H CH₂CONH₂ H CONH₂ H CF₃ F H CH₂CONH₂ HCONH₂ 4-F CF₃ F H CH₂CONH₂ H CONH₂ 5-F CF₃ F H CH₂CONH₂ H CONH₂

or a pharmaceutically acceptable salt thereof.
 14. A compound selectedfrom

and pharmaceutically acceptable salts thereof.
 15. A compound accordingto claim 1 represented by

R⁷ R⁶ R³ R¹ 4-F —CF₃ —CH₃ —CONH₂ 5-F —CF₃ H —CONH₂ H CF₃ —CH₂CH₂OH—CONH₂ H —CF₃ —CH₂CH₂F —CONH₂ H —OCF₃ —CH₂CH₂OH —CONH₂ H —OCF₃—CH₂CH₂CH₂OH —CONH₂ H —OCF₃ —CH₂CONH₂ —CONH₂ H —OCF₃ —CH(CH₃)CONH₂—CONH₂ H —OCF₃ —CH₂CH₃ —CONH₂ H —OCF₃ —CH₂CH₂F —CONH₂ H —CF₃ —CH₂CONH₂—CONH₂ H —OCF₃ —CH₂SO₂NH₂ —CONH₂ 3-F —CF₃ —CH₂SO₂NH₂ —CONH₂ H —CF₃—CH₂CH₃ —CONH₂ H —CF₃ —CH₂CH₂CH₂OH —CONH₂ H —OCF₃ —CH₂CH₂Cl —CONH₂ H—OCF₃ —CH₂CH₂N₃ —CONH₂ H —OCF₃ —CH₂CH₂NH₂ —CONH₂ H —CF₃ —CH(CH₃)CONH₂—CONH₂ H —OCF₃ —CH₂CONHCH₃ —CONH₂ 4-F —CF₃ —CH₂CONH₂ —CONH₂ 4-F —CF₃—CH₂CH₂OH —CONH₂ 4-F —CF₃ —CH₂CH₃ —CONH₂ 4-F —CF₃ H —CONH₂ 5-F —CF₃—CH₂CH₂OH —CONH₂ 5-F —CF₃ —CH₂CONH₂ —CONH₂ H —OCF₃ —CH₂C(═O)CH₃ —CONH₂

or a pharmaceutically acceptable salt thereof.
 16. A compound accordingto claim 1 represented by

R⁴ R³ F H F CH₂CONH₂ F CH₂CH₂OH F CH₃ H H H CH₂CONH₂ H CH₃

or a pharmaceutically acceptable salt thereof.
 17. A compound accordingto claim 1 represented by

R⁶ R³ OCF3 CH₂CONH₂ OCF3 CH(CH₃)CONH₂ OCF3 CH₂CH₂OH OCF3 CH₂CH₂CH₂OHOCF3 CH₂CH₃ CF3 CH₂CONH₂ CF3 CH(CH₃)CONH₂ CF3 CH₂CH₂OH CF3 CH₂CH₂CH₂OHCF3 CH₂CH₃

or a pharmaceutically acceptable salt thereof.
 18. A compound accordingto claim 1 represented by

R³ H CH₂CONH₂ CH₂CH₂OH CH(CH₃)CONH₂ CH₂CH₂CH₂OH CH₂CH₃ CH₂CONHCH₃CH₂CON(CH₃)₂ CH₂CO₂CH₃

or a pharmaceutically acceptable salt thereof.
 19. A compound accordingto claim 1 represented by

R⁷ R⁶ R⁵ R⁴ R³ H OCF₃ H H C(CH₃)₂CONH₂ 5-Cl Cl H H CH₂CONH₂ 4-CF₃ CF₃ HH CH₂COOH 4-CF₃ CF₃ H H CH₂CONH₂ H Cl H H CH₂CONH₂ 3-Cl Cl H H CH₂CONH₂5-CF₃ CF₃ H H CH₂CONH₂ H OCF₃ H H CH(CH₃)COOH H OCF₃ H H CH(CH₃)CONH₂ HCF₃ H H CH(CH₃)CONH₂ H OCF₃ H H

H OCF₃ H H CH(CH₃)COCH₃ H OCF₃ H F CH₂CONH₂ 6-F CF₃ H H CH₂CONH₂ H OCF₃F H CH₂CONH₂ 6-F CF₃ H H CH(CH₃)CONH₂ H OCF₃ F H CH(CH₃)CONH₂ 4-F OCF₃ FH CH₂CONH₂ 4-F OCF₃ F H CH(CH₃)CONH₂ H CF₃ H F CH₂CONH₂ 3-F CF₃ H HCH₂CONH₂ 4-Cl CF₃ H H CH₂CONH₂ H OCF₃ H F CH(CH₃)CONH₂ 6-F CF₃ H HCH₂CONHCH₃ 6-F CF₃ H H CH₂CON(CH₃)₂ H CF₃ H H CH(CONH₂)₂ H OCF₃ H HCH(CONH₂)₂ 6-F CF₃ H H CH(CONH₂)₂ H CF₃ H H CH₂CONHCH₃ H CF₃ H HCH₂CON(CH₃)₂ 4-CF₃ CF₃ H F CH₂CONH₂ H OCF₃ H H CH₂CON(CH₃)₂ H OCF₃ H HCH₂CONHCH₃ H OCF₃ F H CH₂CONHCH₃ H OCF₃ H F CH₂CONHCH₃ 6-F CF₃ H HCH₂CONH(CH₂)₂OH H CF₃ H F CH₂CONHCH₃ H OCH₂CF₃ H H CH₂CONH₂ H OCH₂CF₂CF₃H H CH₂CONH₂ 6-F CF₃ H H

H CF₃ H H

6-F CF₃ H H CH₂CONHCH(CH₃)₂ 6-F CF₃ H H CH₂CONHC(CH₃)₃ H CF₃ H HCH₂CONHC(CH₃)₃ 4-F OCF₃ H H CH₂CONH₂ H CF₃ H H CH₂CONHCH₂CH₃ H CF₃ H FCH₂CONHCH₂CH₃ 6-F CF₃ H H

6-F OCF₃ H H CH₂CONH₂ 6-F CF₃ H H

5-F OCF₃ H H CH₂CONH₂ 6-F OCF₃ H H CH₂COOH H OCF₃ H OCH₂Ph CH₂CONH₂ HOCF₃ H OCH₂Ph CH(CH₃)CONH₂ H CF₃ H H

5-I OCF₃ H H CH₂CONH₂ 6-F CF₃ H H CH₂COCH₃ H CF₃ H H CH₂COCH₃ H CF₃ H H

H CF₃ I I CH₂CONH₂ 5-F OCF₃ H F CH₂CONH₂ 4-F CF₃ H F CH₂CONH₂ H OCF₃ H HCH₂COCH₃ H CF₃ H H

H OCF₃ Br H CH₂CONH₂ H OCF₃ H F CH₂COCH₃ 5-F CF₃ H H CH₂COCH₃ 5-F CF₃ HH

H OCF₃ F H CH₂COCH₃

or a pharmaceutically acceptable salt thereof.
 20. A compound accordingto claim 1 represented by

R⁷ R⁶ R⁵ R⁴ 4-F CF₃ H H 6-F CF₃ H H 3-F CF₃ H H H CF₃ F H H CF₃ H F5-CF₃ OCF₃ H H 4-F OCF₃ H H H OCF₃ F H H OCF₃ H F 4-F CF₃ H F 3-F CF₃ HF H OCH₂CF₂CF₃ F H 4-F OCF₃ F H 4-CF₃ CF₃ H H 5-Cl Cl H H 5-CF₃ CF₃ H H5-F CF₃ H H 4-F OCF₃ H H 5-F OCF₃ H H H OCF₃ H OCH₂Ph H OCF₃ Br H 4-ClCF₃ H H

or a pharmaceutically acceptable salt thereof.
 21. A compound accordingto claim 1 represented by

R⁷ R⁶ R⁵ R⁴ R³ H OCF₃ H H CH₃ H CF₃ H H CH₃ H CF₃ H H H H OCF₃ H H H 4-FCF₃ H H H 4-F CF₃ H H CH₃ 4-F CF₃ H H CH₂CH₂OH 3-F CF₃ H H H 3-F CF₃ H HCH₃ 3-F CF₃ H H CH₂CH₂OH 4-Cl CF₃ H H CH₃ 5-CF₃ CF₃ H H CH₃ 4-Cl CF₃ H HH 5-CF₃ CF₃ H H H 4-F OCF₃ H H H 4-F OCF₃ H H CH₃ 4-F OCF₃ H H CH₂CH₂OH4-Cl CF₃ H H CH₂CH₂OH 5-CF₃ CF₃ H H CH₂CH₂OH H OCH₂CF₂CF₃ H H H HOCH₂CF₂CF₃ H H CH₃ H OCH₂CF₂CF₃ H H CH₂CH₂OH H OCH₂CF₃ H H H H OCF₃ F HH H CF₃ F H H H OCH₂CF₃ H H CH₃ H OCF₃ F H CH₃ H CF₃ F H CH₃ H OCF₃ F HCH₂CH₂OH H CF₃ F H CH₂CH═CH₂ H OCF₃ F H CH₂CH═CH₂ H CF₃ F H CH₂CH═CH₂ HCF₃ F H CH₂CH₂OCH₃

or a pharmaceutically acceptable salt thereof.
 22. A compound accordingto claim 1 represented by

R⁷ R⁶ R⁵ R⁴ R³ H OCF₃ H H CH₂CH₂OCH₃ 6-F CF₃ H H CH₂CH₂OCH₃ 6-F CF₃ H HCH₂CH₂OCH₂CH₃ H OCF₃ H H CH₂CH₂CH₃ H OCF₃ H H CH(CH₂OH)CH₂OH H CF₃ H HCH(CH₂OH)CH₂OH H OCF₃ H H

6-F OCF₃ H H CH(CH₂OH)CH₂OH H CF₃ H F CH(CH₂OH)CH₂OH H CF₃ H FCH₂CH(OH)CH₂OH H OCF₃ H H CH₂CH₂CH₂CH₃ H CF₃ H H CH₂CH(OH)CH₃ 6-F CF₃ HH CH₂CH(OH)CH₃ 6-F OCF₃ H H CH₂CH(OH)CH₂OH H OCF₃ H H

H OCF₃ H H CH₂CH₂CH₂CH₂CH₃ 6-F CF₃ H H

H OCF₃ H H CH₂C(CH₃)₂CH₂OH H OCF₃ H H CH₂CH₂CONH₂ H OCF₃ H H CH₂CH₂SCH₃6-F CF₃ H H CH₂CH₂SCH₃ H OCF₃ H H

H OCF₃ H H CH₂CH₂SO₂CH₃ 6-F CF₃ H H CH₂CH₂SO₂CH₃ 6-F CF₃ H H

6-F CF₃ H H CH₂CH₂CH₂OH 6-F CF₃ H H CH₂SCH₃ 6-F CF₃ H H CH₂CH₂CH₂SCH₃6-F CF₃ H H CH₂CH₂CH₂SO₂CH₃ H OCF₃ H H CH₂CH₂NHCONH₂ 6-F CF₃ H H

H OCF₃ H H CH₂CF₃ H OCF₃ H H CH₂CF₂CF₃ H CF₃ H H CH₂CH₂CH₂OH H CF₃ H H

H OCF₃ H H

H CF₃ H H CH₂SCH₃ H OCF₃ H H CH₂SCH₃ H OCF₃ H H CH₂SO₂CH₃ 6-F CF₃ H HCH₂SO₂CH₃ 6-F CF₃ H H CH₂CH₃ 6-F CF₃ H H CH₂CH₂CH₃ H OCF₃ H HCH₂SO₂NHC(CH₃)₃ H OCF₃ H H CH₂SO₂NH₂ H OCF₃ H H

4-F CF₃ H H CH₂SO₂NH₂ H CF₃ H H CH₂SO₂NH₂ 4-F OCF₃ H H CH₂SO₂NH₂ 6-F CF₃H H CH₂SO₂NH₂ H CF₃ H H CH₂SO₂CH₃ H OCF₃ F H CH₂SO₂CH₃ 4-F CF₃ H HCH₂CH₃ 4-F OCF₃ H H CH₂CH₂CH₂OH 4-Cl CF₃ H H CH₂SO₂NH₂ 3-F CF₃ H HCH₂SO₂NH₂ 4-F CF₃ H H CH₂SO₂NHCH₃ H CF₃ H F CH₂CH₂CH₂OH H OCF₃ F HCH₂CH₂F H OCF₃ H F CH₂CH₂F 4-F OCF₃ F H CH₂CH₂F 6-F CF₃ H H CH₂CH₂F HCF₃ H F CH₂CH₂F 4-CF₃ CF₃ H H CH₂SO₂NH₂ H OCF₃ H F CH₂SO₂NH₂ H CF₃ H FCH₂SO₂NH₂ H OCF₃ H F CH₂SO₂NHCH₃ H CF₃ H F CH₂SO₂NHCH₃ H CF₃ H H CH₂CH₂FH OCF₃ H H CH₂CH₂F 3-F CF₃ H H CH₂CH₂F 4-Cl CF₃ H H CH₂CH₂F 5-CF₃ CF₃ HH CH₂CH₂F H OCF₃ F H

H OCF₃ H F CH₂CH₂F H OCF₃ F H CH₂CH₂F 5-F CF₃ H H CH₂CH₃ 5-F CF₃ H HCH₂CH₂F H CF₃ H H CH(CONH₂)₂ H OCF₃ H H CH(CONH₂)₂ 6-F CF₃ H HCH(CONH₂)₂ 6-F CF₃ H H CH₂CONHCH₂CH₂OH

or a pharmaceutically acceptable salt thereof.
 23. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier.
 24. (canceled)
 25. A method oftreatment or prevention of pain comprising the step of administering toa patient in need thereof a therapeutically effective amount, or aprophylactically effective amount, of a compound according to claim 1,or a pharmaceutically acceptable salt thereof. 26-37. (canceled)
 38. Apharmaceutical composition comprising a therapeutically effective amountof a compound according to claim 2, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.
 39. (canceled)40. A method of treatment or prevention of pain comprising the step ofadministering to a patient in need thereof a therapeutically effectiveamount, or a prophylactically effective amount, of a compound accordingto claim 2, or a pharmaceutically acceptable salt thereof. 41-52.(canceled)